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MicroRNA has emerged as a potential biomarker for cancer detection and treatment. This is because a large number of studies have definitely indicated miRNAs as a key player in cancer pathomechanism. This review provides two of dysregulatory mechanisms underlying cancer in which miRNAs play a central role including miRNA gene mutation and aberrant miRNA biogenesis as well briefly reporting miRNA biogenesis.
MicroRNAs (abbreviated miRNAs) are firstly identified in C. elegans in 1993, and today people have found miRNAs in most organisms (Rooij .V and Eva, 2011; Santulli and Gaetano, 2015). MiRNAs are characterized to be non-coding RNAs with a tiny size of about 22 nucleotides in a cell (Cai et al. 2009) and proved to be vital players in the negative regulation of gene expression (Santulli and Gaetano, 2015). MiRNAs significantly contribute to a variety of biological processes especially cell proliferation, differentiation and apoptosis in which abnormalities of miRNA function may cause cancer (Zhang et al. 2007; Santulli and Gaetano, 2015). Additionally, after a breakthrough revealed a correlation between miRNA and cancer in 2003 (Rooij and Eva, 2011), a research of Calin et al. in 2006 showed that the percentage of miRNA genes residing in fragile sites or cancer-related genomic area is up to over 50 percents. Another strong evidence of miRNAs’ role in cancer is served dysregulation of miRNAs. As a result, miRNAs are concerned as an important target in pathomechanism investigation and therapeutic invention in oncology. This paper reviews the previous literature to answer a research question: How do miRNAs involve in cancer formation? Although cancer-relevant miRNA detects are identified in a range of dysregulatory mechanisms, the review focus on two themes including miRNA gene mutation and aberrant miRNA biogenesis. Furthermore, biological synthesis of miRNAs is briefly reported in the paper.
Synthetic process of miRNAs occurs in both nucleus and cytoplasm with help of various proteins. In the nucleus, prior-miRNAs, large primary transcripts possessing a 5’ cap and 3’ polyadenylated tail, are transcribed by RNA polymerase II. Then the prior-miRNAs are sliced into a pre-miRNA with stem-loop shape containing about 85 nucleotides by a DGCR8/RNase Drosha III complex. Following exportation of the pre-miRNAs into the cytoplasm by a couple-protein complex called RanGTP/Exportin 5, miRNA/miRNA duplex with ~ 20 – 22 nucleotides in length is generated through processing the pre-miRNAs by RNase III Dicer and a peer protein TRBP. After that, a strand named mature miRNA is separated from miRNA/miRNA duplex and then bind protein complex RISC and orientate RISC to mRNA target (Peng and CRobe, 2016).
Involvement of MiRNAs is discovered in two biological processes: gene expression regulation and signaling pathway. Regarding inhibition of gene expression, in a majority of situations, miRNAs are complementary with mRNA target at 6-8 nucleotide region near 5’ end of the miRNAs called seed region. Complementarity of mRNA targets and miRNAs at seed region is coined Watson – Crick pairs (Bartel, 2009). In other situations, a recent research conducted by Helwak et al. found an alternative complementary side between miRNAs and cognate targets by using technique CLASH, and this side is independent of seed region. Consequently, if the interaction between miRNAs and mRNA targets is caused by imperfect complementarity, translation of the target will be repressed. In another case, a perfect base pairing leads to degradation of mRNAs. Turning to miRNA role in the signaling pathway, it is indicated that miRNAs portraying a ligand bind to Toll-like receptors, which may indirectly activate tumor growth and metastasis (Fabbi et al).
Biogenesis of miRNAs is under a tight control at the levels including miRNA transcription, miRNA processing, miRNA transportation, miRNA function with the regulation of a range of proteins
Dysregulation mechanisms of miRNAs in cancer
MiRNA synthesis experiences a tight control at many levels with the involvement of a range of proteins. Through a series of studies over past ten years dysregulation of miRNA expression has clearly known as one of the core causes of cancer formation. MiRNA gene mutation and aberrant miRNA biogenesis are two of fundamental mechanisms belong to miRNA dysregulation.
Aberrant miRNA biogenesis
As described above, a series of enzymes and proteins such as Dicer, Drosha, DGCR8, exportin 5, Argonaute proteins, etc. enroll apparatus of miRNA genesis to manipulate and regulate a formation of miRNAs as well correcting mistakes during a course from pri-miRNAs to mature miRNAs. Therefore, if any deviant behaviors of components in the machine due to mutation or abnormal expression arise unexceptionally, miRNAs will be expressed aberrantly.
Regardless of Drosha and Dicer, these RNA polymerase III involving in prior-miRNA and pre-miRNA processing are observed to be uncontrolled in several tumors. In particular, Walz et al. discovered that 15% of 534 Wilms’ tumors have Drosha and DGCR8 with substitution or deletion mutations at a single nucleotide, which negatively impacts the expression of mature Let -7a and miR-200 family. Other study found that Dicer1 decrease in colorectal cancer cells activates tumor formation and metastasis. Furthermore, there is a correlational research on the relationship between the level of Dicer/Drosha and median survival in ovarian cancer. The study identified that if the expression level of Dicer is high, sufferers have higher survival rate. Study of Karube et al. also revealed a positive correlation between Dicer content and let-7 expression in lung cancer.
Turning to Argonaute (AGO) proteins which catalyze RISC and support RNA-silencing process, lose of Argonaute protein coding EIF2C1/hAgo1 gene often occurs in Wilms’ tumors of the kidney. Another example of Argonaute proteins’ impact in cancer, a level of AGO2 gene expression in primary gastric cancer and lymph node metastases is higher than that in control samples.
According to a study by Melo et al., exportin 5 (XPO5) which takes responsibility for pre-miRNA transportation to cytoplasm are not expressed due to an inactivating genomic change in XPO5 gene. This leads to accumulation of pre-miRNAs in the nucleus and reduces expression of miRNAs.
MiRNA gene mutation
Deletion of miR-143 and miR-145 gene located on 5q33 area was often observed in lung cancer, causing reduction of these gene expressions (Calin). Besides of that, miR-17-92 cluster gene is amplified in B cell lymphomas and lung cancer, which leads to overexpression of miRNAs coded by miR-17-92. There are not only two above findings but also many pieces of evidence of miRNA mutation found in various cancers. This highly frequent miRNA gene mutation was also confirmed by experiment in which 227 specimens loading samples from ovarian cancer, breast cancer, and melanoma were tested by using high-resolution array-based comparative genomic hybridization. Further study revealed a half of miRNA genes reside in fragile sites or cancer-related genomic area. Overall, miRNA mutation genes cause abnormal expression of miRNA which generally leads to malignancy. Amplification and deletion are two popular forms of mutation in miRNA genes and these genomic changes occur high frequently (Peng and Crobe, 2016).
Thanks to advanced sequencing technology, abnormal miRNA genes were identified in a variety of malignancies, which is the first clue for a hypothesis of miRNA role in cancer and further research of pathomechanics and therapeutic discovery. This paper has answered a part of the research question in term of gene mutation and misregulation of miRNA biogenesis as well as summarizing how miRNAs are generated and how they function. Based on knowledge gained from this review, I have hypothesized that
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Not all tumors are cancerous; benign tumors do not spread to other parts of the body. Possible signs and symptoms include a lump, abnormal bleeding, prolonged cough, unexplained weight loss, and a change in bowel movements. While these symptoms may indicate cancer, they may have other causes. Over 100 types of cancers affect humans.
Factors Responsible for Cancers:
Exposure to particular substances has been linked to specific types of cancer. These substances are called carcinogens.
Tobacco smoke, for example, causes 90% of lung cancer. It also causes cancer in the larynx, head, neck, stomach, bladder, kidney, esophagus and pancreas. Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons. Tobacco is responsible for about one in five cancer deaths worldwide.
Diet and exercise:
Diet, physical inactivity and obesity are related to up to 30–35% of cancer deaths. Physical inactivity is believed to contribute to cancer risk, not only through its effect on body weight but also through negative effects on the immune system and endocrine system. More than half of the effect from diet is due to over nutrition (eating too much), rather than from eating too few vegetables or other healthful foods.
A high-salt diet is linked to gastric cancer.
Aflatoxin B1, a frequent food contaminant, causes liver cancer.
Betel nut chewing can cause oral cancer.
Worldwide approximately 18% of cancer deaths are related to infectious diseases. Viruses are the usual infectious agents that cause cancer but cancer bacteria and parasites may also play a role.
Oncoviruses (viruses that can cause cancer) include human papillomavirus (cervical cancer), hepatitis B and hepatitis C viruses (hepatocellular carcinoma).
Bacterial infection may also increase the risk of cancer, as seen in Helicobacter pyloriinduced gastric carcinoma.
Parasitic infections associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder)
Up to 10% of invasive cancers are related to radiation exposure, including both ionizing radiation and ionizing ultraviolet. Additionally, the majority of non-invasive cancers are nonmelanoma skin cancers caused by non-ionizing ultraviolet radiation, mostly from sunlight.
Sources of ionizing radiation include medical imaging and radon gas.
Non-ionizing radio frequency radiation from mobile phones, electric power transmission and other similar sources has been described as a possible carcinogen by the World Health Organization’s International Agency for Research on Cancer.
The vast majority of cancers are non-hereditary (sporadic). Hereditary cancers are primarily caused by an inherited genetic defect. Less than 0.3% of the population are carriers of a genetic mutation that has a large effect on cancer risk and these cause less than 3–10% of cancer.
Some of these syndromes include: certain inherited mutations in the genes BRCA1 and BRCA2 with a more than 75% risk of breast cancer and ovarian cancer, and hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome), which is present in about 3% of people with colorectal cancer.
A prominent example of this is prolonged exposure to asbestos, naturally occurring mineral fibers that are a major cause of mesothelioma (cancer of the serous membrane) usually the serous membrane surrounding the lungs. Other substances in this category, including both naturally occurring and synthetic asbestos-like fibers, such as wollastonite, attapulgite, glass wool and rock wool, are believed to have similar effects.
Non-fibrous particulate materials that cause cancer include powdered metallic cobalt and nickel and crystalline silica. Usually, physical carcinogens must get inside the body (such as through inhalation) and require years of exposure to produce cancer.
Some hormones play a role in the development of cancer by promoting cell proliferation. Insulin-like growth factors and their binding proteins play a key role in cancer cell proliferation, differentiation and apoptosis, suggesting possible involvement in carcinogenesis.
Hormones are important agents in sex-related cancers, such as cancer of the breast, endometrium, prostate, ovary and testis and also of thyroid cancer and bone cancer.
Osteosarcoma may be promoted by growth hormones. Some treatments and prevention approaches leverage this cause by artificially reducing hormone levels and thus discouraging hormone-sensitive cancers.
Modes of Treatment:h3>
Radiation therapy (also called radiotherapy) is a cancer treatment that uses high doses of radiation to kill cancer cells and shrink tumors. At low doses, radiation is used in x-rays to see inside your body, as with x-rays of your teeth or broken bones.
Chemotherapy (also called chemo) is a type of cancer treatment that uses drugs to kill cancer cells. Chemotherapy works by stopping or slowing the growth of cancer cells, which grow and divide quickly.
Chemotherapy not only kills fast-growing cancer cells, but also kills or slows the growth of healthy cells that grow and divide quickly. The most common side effect is fatigue, which is feeling exhausted and worn out
Targeted therapy is the foundation of precision medicine. It is a type of cancer treatment that targets the changes in cancer cells that help them grow, divide, and spread.
Most targeted therapies help treat cancer by interfering with specific proteins that help tumors grow and spread throughout the body. They treat cancer in many different ways. They can:
Help the immune system destroy cancer cells.
Stop cancer cells from growing.
Stop signals that help form blood vessels.
Deliver cell-killing substances to cancer cells.
Cause cancer cell death.
Hormone therapy is a cancer treatment that slows or stops the growth of cancer that uses hormones to grow. Hormone therapy is also called hormonal therapy, hormone treatment, or endocrine therapy.
The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial.
Cancer. Whenever people think about cancer they only think about the disease, the growth, and the tumors. What society fails to see is the victim behind the disease. People are always so concerned about “curing” the disease the victim of cancer is forgotten. Treating the disease has become more important than treating the patient and their innate needs as a human. In breast cancer patients’ treatments such as chemotherapy, and locoregional therapy cure the cancer but there are physical and psychological side effects that are not “cured” at the same time and can have lasting effects on a breast cancer patient’s life.
One common treatment for breast cancer is chemotherapy. Several chemotherapy drugs have been in use since the 1960’s. Combination chemotherapy became the standard treatment, which means multiple chemotherapy drugs are given to the patient at a time. The main drugs used are cyclophosphamide, epirubicin, fluorouacil, methotrexate, mitomycin, mitozantrone, doxorubicin, docetaxel, and gemcitabine. Chemotherapy can be used before or after surgery. Getting it before surgery can make the tumor smaller which can mean less surgery, for example only having the tumor removed instead of a full mastectomy. Chemotherapy can be used after surgery for multiple reasons such as the cancer cells were high grade, or more commonly, if there is a possibility that the cancer spread to other parts of the body. In this case, chemotherapy is used as a preventative measure to reduce the chances of the cancer coming back.
Some chemotherapy drugs are taken orally, but most are administered by IV. The treatment is administered in cycles. One cycle typically consists of one to five days of taking the drugs, then a break for three to four weeks, another few days of drugs, then a break. A typical course of treatment contains up to eight cycles and will take up to eight months. However, more courses could be recommended based on the type of breast cancer, and the combination of drugs used.
Locoregional therapy, which is a therapy that is restricted to a localized region of the body, is most commonly used as a treatment for Breast Cancer in the form of the mastectomy. With a mastectomy, partial or the entire breast is removed due to the cancer mass. This wasn’t always the best option though. “For almost a century, the Halsted radical mastectomy was the standard surgical treatment for breast cancer. Women receiving this treatment suffered terrible cosmetic deformity, with loss of arm function through resection of the pectoral muscles, high risk for lymphedema as the result of extensive axillary nodal dissection, and significant pain and tightness across the chest wall.”(Ganz) New locoregional therapy has developed into using radiation in the localized region to take care of the mass without having to remove the breast issue. It was less invasive, but recently, there was an increase of mastectomies because there were changes made to the techniques that have less side effects. “The recognition of the biologic significance of locoregional recurrence as an indicator rather than an instigator of increased risk for distant disease was an important step in better understanding breast cancer biology with significant clinical implications. “Systemic chemotherapy at the time of locoregional recurrence was formally evaluated in a recent randomized clinical trial that demonstrated significant improvement in disease-free survival and overall survival for this poor-prognosis group”(Wiernik). With this therapy, there is less effect on the rest of the body, but there are still major side effects, as with any therapy.
There are so many ways to treat cancer. But in every form of treatment, there are a lot of side effects. From chemotherapy and radiation, patients have to endure painful and tiring side effects of their treatment. Some chemotherapy drugs, since they are composed of chemicals, can cause nerve and muscle damage or fertility problems. It can also cause hair loss, easy bruising and bleeding, infection, anemia, nausea and vomiting, appetite changes, constipation, diarrhea, skin and nail changes such as dry skin and color change, urine and bladder changes and kidney problems, weight changes, problems with concentration, mood changes, changes in libido and sexual function, and mouth, tongue, and throat problems such as sores and pain with swallowing.
Radiation can give patients some of the same side effects as those of chemotherapy. Some of the side effects can show up during or after the treatment. Some can show up years or months later. Some may or may not be permanent. If the treatment for the breast cancer is to get a mastectomy, there are the physical side effects of the pain from the surgery itself. When you get a mastectomy, even a double mastectomy, you still might have to go through some of the other forms of treatment such as chemo and radiation. The cosmetic changes in the breast(s) that result from surgeries such as mastectomies have many long term effects from this can influence one’s psychological health.
The devastating physical effects of breast cancer are more so known than the psychological implications. Cancer in general has many psychological effects regarding the patient’s understanding and ability to cope with the disease, the prognosis, as well as the complexity and options of treatment (Ganz, pg 1). Cancer often brings psychosocial distress (Ganz, pg 2). However, breast cancer, due to the sometimes-traumatic transformation after life saving surgery, can have very detrimental psychological impacts. A patient’s social identity and self-concept often shift completely (Your Body After Breast Cancer Treatment). Women who have survived breast cancer after having a mastectomy or some kind of reconstructive surgery often experience a shift in body image and a change in self perception of their own sexuality (Ganz, pg 1, 2). Social Identity theory is defined as a “person’s sense of who they are based on group membership” and often times women feel that they lose their sense of femininity and by result their sense of identity (McLeod).
The ways to cope with the sudden dramatic changes from the lifesaving surgery can be confronted through counseling, support systems to improve one’s psychosocial health, and with help from one’s doctor (Your Body After Breast Cancer Treatment). The sooner the patient comes to terms with the changes due to their treatment the better their long term healing and understanding will be. Body positivity is an important coping mechanism as well. It is important to remain cognitively positive when overwhelmed with the negative changes that occur. Focusing on three things you like about yourself before examining oneself after the surgeries will help to increase one’s own image (Your Body After Breast Cancer Treatment, pg 1). For patients that have difficulties coping with or coming to terms with their new appearance and therefore their new self concept or identity, often feel more comfortable exploring breast reconstruction surgical options in an attempt to retain their previous self image (Your Body After Breast Cancer Treatment, pg 1 & Ganz, pg 1).
In the final analysis, women with breast cancer are defined more than by the disease they have. They can be cured from the growth, from the tumor, from the cancer but are not cured from the other physical and psychological long term side effects of the cancer. The breast cancer patient is victimized by societies inabilities to realize the cure is well beyond the tumor but instead the healing is more psychological from the change in identity and body image the patient once had.
Breast cancer is the most common cancer in women worldwide and its incidence rate is increasing, especially in developing countries. This malignancy is one of the most common causes of death in women all around the world. The mean age of diagnosis in Western countries is around 50 – 60 years and it is accounted the fifth most common cause of cancer related death.
As other parts of the world, this malignancy has the first grade among the common cancers in women in Iran and some studies have shown that it occurs in the Iranian women at least one decade younger on average compared to the case in Western countries. In addition, breast cancer has the most years lost due to disability (YLD) in Iran, because it develops at lower age and is diagnosed at higher stage. Nonetheless, reports imply that survived patients will double by 2030. This might be owing to improvements in diagnostic techniques and general population awareness in this area. However, cancer diagnosis and treatment process can affect physical, psychological, sexual and social health of women.
Treatment completion and cure may be considered as elimination or halting cancer development from physician’s point of view, while it almost conveys several health related problems and worries for the patient and her family. Findings show that the hardest period for women with breast cancer is prior to treatment initiation, and treatment completion.
For these patients the most important psychosocial stress is solitude that takes place after definite diagnosis, during the treatment period, and after completing the treatment. Breast cancer patients may suffer from fatigue, nausea, vomiting, appetite loss, diarrhea, acute and/or chronic pain, sleep disorders, oral cavity mucosal wounds, hair loss and reproductive disorders, such as atrophic vaginitis, ovarian dysfunctions, including infrequent or absence of menstruation, sub- fertility, and infertility. Furthermore, as the breasts are counted for sexual arousal and are counted to attractiveness, important part of feminine identity and maternal role, facing a situation that may result in loosing breast may lead to disorders including loss of self-confidence, self-body image damage, alteration of marital relations, sexual enjoyment and depression. Reports from limited studies in Iran imply that women with breast cancer attempt to cope with the illness and treatment side-effects by various strategies.
Some patients tend to share their painful experiences and intrusive thoughts with others, seek help from family and friends’ emotional supports or try to find the answers of their questions by asking healthcare providers about their illness to adopt to the illness; whereas, some of them resort to maladaptive responses such as anger, fear, sense of sin, isolation, and even denying the illness and seeking for treatment. However, it is not definitely clear which coping ways are most applied by patients and what kinds are most effective to diminish cancer related disorders to adjust with the situation in the process of the illness.
Furthermore, different personal characteristics among patients affect confronting their response to cancer diagnosis, acceptance or rejection of the illness, and strategies to adjust with the cancer . Coping strategies include efforts those patients apply to eliminate or decrease the impacts of stressful events and achieve adaptation. Coping usually is a process from a crisis to adaptation and deals with a stressor. There are two main coping strategies: Problem-focused and emotional-focused. The first involves effective actions for decreasing or amending stressful conditions and the second attempts to regulate the emotional outcomes and affective balance by controlling the emotion resulted from stressful circumstances
However, there is this third coping style that identifies unadjusted coping strategies which lead to failure against the tensions, disorder in daily activities and continuous applying, all making the situation to be more critical. Thus, being aware of whether each patient has been able to adjust with the stress through wide spectrum of illness, from facing suspicious symptoms, definite diagnosis, treatment and follow up, is necessary for medical staffs to facilitate the recovery and help patients to promote psychological healing.
To date, some standardized inventories have been introduced and used in several studies to assess coping behaviors in patients with cancer , but none of them are specific to breast cancer. As evaluation of various aspects of women’s health by standardized and specific instrument is one of the common methods of assessments, being specific and culturally sensitive of each instrument should be considered in every setting appropriately; otherwise, generalizability of the findings might be diminished. According to the variations of coping behaviors among cancer patients with different cultural beliefs, it is necessary to design a specific instrument based on the exploration through deep layers of individuals’ experiences and perceptions. When there is no sufficient or available inventory for this purpose, the researcher needs to design an instrument. Using sequential exploratory strategy is often an elective method, in that researcher gathers and analyze necessary data on the basis of a qualitative approach, design the initial instrument and use it in the target population.
Learning Objectives Describe the medical and wellness models of health. List the key points of the World Health Organization definition of health. List and describe the six dimensions of wellness. List the three health behaviors responsible for most of the actual causes of death. Define lifestyle disease.
The Definition of Health
Learning Objectives (continued) Identify the goals of Healthy People 2020. List and describe the major health issues of college students. Describe the Health Belief Model, Transtheoretical Model, and Theory of Reasoned Action/Theory of Planned Behavior.
The Definition of Health
Models of Health Dimensions of Health and Wellness Lifestyle Diseases The U.S. Medical Care System Healthy People 2020 Health Issues of College Students Making Healthy Lifestyle Changes
The Definition of Health
What is your definition of health? Wellness? Are they the same for everyone in the class? What are the most important things that characterize what we think of as health?
The Wellness Model of Health
There are many aspects that people bring into health; it is impossible to define or measure health but there are certain things that go with the term health. World Health Organization defines health as “a state of complete physical, mental, and social well-being and not merely the absence of disease and infirmity.”
The Wellness Model of Health
Health is a dynamic process that is affected by the decisions we make every day. It is a way of life.
The Wellness Model of Health
Medical model Wellness model
Models of Health
Health incorporates three ideas: Being free from symptoms of disease and pain as much as possible. Being active, able to do what you want and do what you must at the appropriate times. Being in good spirits and feeling emotionally healthy most of the time.
Wellness Model of Health
Medical Model Health is the absence of one or more of the “five Ds”: death, disease, discomfort, disability, and dissatisfaction. Relies almost exclusively on biological explanations of disease and illness and on interpreting them in terms of malfunction.
Models of Health
measure the health status of a population.
describes the predominance of a disease in a population.
means the occurrence of particular diseases; the frequency at which certain diseases occur; the number of people who contract a disease or illness within a specifically given period of time.
data are statistics on the number of people suffering from illness in a given population.
data are the number of deaths in a given population.
The wellness model encompasses the physiological, mental, emotional, social, spiritual, and environmental aspects of health. It emphasizes self-healing, the promotion of health, and the prevention of illness rather than solely the treatment of disease. (many believe in self healing)
requires understanding emotions and coping with problems that arise in everyday life.
involves having a mind open to new ideas and concepts. Spiritual wellness is the state of harmony between you and others.
is being able to enjoy what you are doing to earn a living or to contribute to society.
is the ability to perform social roles effectively, comfortably, and without harming others.
is a healthy body maintained by eating right, exercising regularly, avoiding harmful habits, making informed and responsible decisions about health, seeking medical care when needed, and participating in activities that help to prevent illness.
Today’s “lifestyle diseases,” chronic diseases caused by lifestyle behaviors, are the leading causes of illness and death. Taking responsibility for our behaviors means changing our negative lifestyles to positive lifestyles; by doing so, we can avoid illness and achieve wellness, or optimal health.
This graph represents the number of preventable deaths in the year 2010.
Approximately half of the 2.6 million deaths in the United States each year are due to lifestyle factors. Leading the list of life-shortening behaviors is tobacco use, which is responsible for more than 446,000 deaths among Americans per year.
Unhealthy diet and activity patterns contribute to the next highest number of deaths in the United States after tobacco: Associated with heart disease, high blood pressure, stroke, diabetes, and cancer. Alcohol abuse accounts for close to 48,000 deaths each year. Some of these deaths are attributed to environmental factors, such as agents that people are exposed to in the workplace and elsewhere.
Type 2 Diabetes as a Lifestyle Disease Type 2 diabetes (non-insulin-dependent) was formerly referred to as “maturity onset” diabetes. Often is associated with being overweight. Currently, 26 million Americans have diabetes, and many more have prediabetes, which means they might develop diabetes in the next 10 years. For every 20% increase in weight gain, the chance of diabetes doubles.
Type 2 Diabetes as a Lifestyle Disease (continued) Research has conclusively shown that eating healthfully and engaging in moderate physical activity can both reverse and prevent type 2 diabetes. Many contestants on the show “The Biggest Loser” start out on medication for diabetes and leave the show not needing it. That is amazing!
Nearsightedness often occurs when vision is affected by lifestyle. During early development, a child’s eyes adapt to the visual information they receive from the environment. Watching TV and computer screens closely, and reading books, magazines, and newspapers for many hours daily, cause myopia.
Lifestyle Diseases Nearsightedness
The Medical model of health has given rise to a massive industry of medical care. Many refer to our current medical care system as sick care because it focuses on those who are already sick and lacks focus on keeping individuals well. Americans spend twice as much per capita on medical care than other medically developed countries.
The U.S. Medical Care System
Medical care should focus on keeping people well. The Affordable Care Act went into effect in 2013 and aims to provide everyone access to medical care regardless of income, age, and health status.
The U.S. Medical Care System
This is the government’s health objectives for the nation to achieve by the year 2020. Goals: Help all people live longer and improve the quality of their lives. Eliminate health disparities among segments of the U.S. population.
Healthy People 2020
It consists of 1,500 specific health objectives grouped into 42 topic areas. Healthy People 2020 was developed with a greater understanding of advances in preventive services such as vaccinations and other pharmaceuticals, assistive technologies, computerized systems, and heightened awareness and demand for preventive health services and quality health care.
Healthy People 2020
Topic Areas for Healthy People 2020
Healthy People 2020
Foundation Health Status
Healthy People 2020
College students are affected by specific health issues that are unique to their stage of life. Some of these issues affect students of any age such as time pressure, academic stress, and financial stress. Some health issues, such as the risk of STDs, are more pertinent to students within a specific age group.
Health Issues of College Students
A major assumption of the health education system is that nearly everyone has a basic desire to be healthy and well, but many acquire habits of thoughts and behaviors that make them less well rather than more. Health Belief Model Transtheoretical Model Theory of Reasoned Action/Theory of Planned Behavior
Making Healthy Lifestyle Changes
Expectations For Success People pursue goals with expectations about the outcomes of their efforts. Optimism motivates whereas pessimism stifles. Name one goal that you have in terms of health. Make sure it is measurable and attainable in a reasonable amount of time. Name two or three strategies for action that will help to accomplish that goal. Describe how having an optimistic versus a pessimistic outlook can affect the success of that goal.
Making Healthy Lifestyle Changes
Positive thoughts promote healthy behaviors, decreased risk of disease, and longer life when transformed into action through: Goals Strategies for action Agency Expectations for success
Making Healthy Lifestyle Changes
Are making note of things that you want to do or things that you want to avoid. Setting goals can help motivate change.
Making Healthy Lifestyle Changes Goals
Are the plans generated for attaining the goals that have been set. Help determine whether a goal is attainable.
Making Healthy Lifestyle Changes Strategies for action:
Is the belief that one can influence the nature and quality of one’s life, rather than believing that one’s fate is determined by reacting to circumstances not in one’s control.
Making Healthy Lifestyle Changes Agency
Was developed to explain and predict preventive health behavior. Also includes general health motivation for the purpose of distinguishing between illness and sick-role behavior from healthy behavior.
Making Healthy Lifestyle Changes Health Belief Model
Health Belief Model (continued) Factors include: Perceived susceptibility An individual’s perception of how susceptible he or she is to disease. Perceived seriousness The belief a person holds concerning the effects of a given disease or condition.
Making Healthy Lifestyle Changes
Health Belief Model (continued) Factors include: Perceived benefits of taking action After accepting the susceptibility and seriousness, the action a person chooses is affected by his or her perception of how much the action will outweigh the costs.
Making Healthy Lifestyle Changes
Health Belief Model (continued) Factors include: Barriers to taking action An action may not take place even though the person believes in its benefit because of barriers such as cost, time, pain, etc. Cues to action Internal or external motivators
Making Healthy Lifestyle Changes
Acknowledges that behavior change go through the following stages.
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Person is not considering change at any time in the foreseeable future
Person is aware that change is desirable but has not committed to act.
Person desires change and commits to do so in the near future.
Person starts a change.
Person strengthens the change, realizing that even when a lapse occurs, he/she will not consistently return to the old behavior
Person is no longer tempted to return to the previous behavior.
Changing a health behavior begins with an intention to adopt a new behavior. This intention is a combination of positive attitude about the new behavior and a perception of how others will respond to the new behavior. Change is affected by how much control the person thinks he/she has over changing the behavior.
Theory of Reasoned Action/ Theory of Planned Behavior
Choosing a healthy lifestyle is up to each individual.
A Healthy Lifestyle
Don’t smoke. Get seven to eight hours of sleep per night. Maintain a healthy body weight. Get regular exercise. Consume little or no alcohol. Eat breakfast regularly. Minimize snacking between meals.
Things you can do to stay healthy
1. no tobacco 2. eat right 3. be sun smart 4. exercise 5. find it early
FIVE STEPS TO CANCER PREVENTION
Tobacco is responsible for 90% of Lung Cancers
* Tobacco products are some of the most potent toxins known * Includes all forms : cigarettes, pipes, cigars, chew, plug and Dip * Accounts for 1 out of 5 deaths in the USA * Connection between tobacco use and cancer is proven. No Natural History studies done at this time due to dire consequences for participants.
Healthy substances vs. Harmful substances * Some substances in foods are fast acting while others are slow to act. Carcinogens (cancer causing agents) in food often take 10 – 20 years to act. * Some foods have protective substances ,(fruits,vegetables and whole grains). * All foods high in fiber/low in fat help protect body cells from cancer.
* Melanoma is increasing annually and faster than any other type of cancer in the USA. It remains a big problem for Americans all over the country. * Constant exposure to UV light causes “Immunosupression” , which makes us more susceptible to all cancers and many other diseases. * Many people receive major DNA damage from the sun before the age 18. Skin damage from the sun is cumulative over the years. * Skin Cancer is most preventable: A) Avoid direct exposure to midday sun (10-3). B) Cover up exposed body parts (Adults and especially Children). C) Use a Suncreen of at least SPF 15 (Sun Protection Factor).
Be Sun Smart
* Regular Exercise reduces the risk of getting cancer * Strenous exercise while good , is not necessary . A brisk walk daily for 30 minutes will be quite adequate. * Start exercise programs slowly and check with your physician before starting.
* The earlier cancer is found , the easier it is to treat . * Due to early detection , the survival rate for cancer has increase over the years from 38% to over 60% , since 1966, for all types of cancer. * “You” are the most important factor in detecting cancer early thru : A) Breast Self Exams (monthly) B) Testicular Self Exams (monthly ) C) Skin Self Exams (monthy) D) Annual visits and checkups with your Physician . E ) Over 10 Million people have been successfully treated for cancer. F) 75-85% of all Cancers are caused by Lifestyle choices we make.
Carcinogen is better known as substances capable of causing cancer in living tissue. From looking at our lecture notes, we learn that the cancer rate increased tremendously from 1900 to 1990.People can inherit cancer genetically or from natural exposure. It is said and believed that substances that we use daily can cause us to be exposed to cancer. According to the American Cancer Society, environmental factors can include a wide range of exposures, such as nutrition, medical treatments, workplace exposure, pollution, household exposures, and naturally occurring exposures. Scientists often experiment on animals and cell cultures to determine what may cause different types of cancers. I do not feel as though new chemicals undergo proper or sufficient testing before it is marketed.
One such chemical that might unfortunately go overlooked is arsenic. Arsenic in drinking water can cause liver, bladder, lung, skin, and kidney cancer. Yet, the most frightening reality to me is how many chemicals and “toxins” currently lace our foods for the sake of stretching a corporate dollar by extending shelf life as long as they can. An infamous example of a chemical added to our food that warrants greater alarm is Bromated Vegetable oil, aka “BVO.” Bromated vegetable oil is a common additive to many bottled sodas, sports drinks, and many citrus-flavored drinks. Unfortunately, BVO is known for increasing cholesterol levels, and repeated consumption can also wreak major damage to one’s liver and kidneys.
Another particular group of chemicals that truly ought to be left off the dinner plate is Benzoate Preservatives, also informally known as, “BHT, BHA, TBHQ.” These chemicals have definite links to hormonal imbalance, urticaria, increased risk of cancer, hyperactivity, and asthma. You may find these chemicals “lying in wait” in your favorite cereals, gum varieties, nut mixes, certain brands of butter, and even packages of raw meat. Aflaxtoxins, Aminobiphenyl, Asbestos, and Azathiorprine are to name a few other dangerous inorganic substances used in the most commonplace everyday products that cause cancer. These products make up an ever-growing list, and include names like Johnson and Johnson baby powder, Ajax, Lysol, Oscar Mayer beef franks, and Crest toothpaste etc. As the studies demonstrate, carcinogens are no laughing matter.
I find it both disheartening as well as sickening just how many chemicals are introduced into our environment without thorough scientific testing taking place. Cancer is a disease that affects so many families, and, rather tragically, it is often diagnosed in individuals far too late for treatment. I have a close friend who I consider family; her sister who was 15 at the time was diagnosed with Stage 4 brain cancer. If only we would stop and be more concerned with the chemicals we use on the daily basis. Carcinogens are a real danger to one’s health. As it accumulates in the human body in large amounts, there is a high chance that cells will become damaged, resulting in the growth of cancer cells. The chemicals we ingest into our body through food consumption, and the chemicals we inhale via cleaning products are causing a lot of damage to us. You might not see it today or a few months from now but you will definitely see the consequences in the future.
A common type of cancer is lung cancer, which starts by the mutation of DNA and uncontrolled growth of mutated cells in at least one lung. These mutations are caused by factors including breathing in cigarette smoke and being exposed to radon gas. As its name implies, lung cancer affects the lungs. It can potentially spread from one part of a lung to covering all of both lungs if malignant tumors are present. Lung cancer is most prominent in people over the age of sixty, but sometimes it can start years prior. There are four stages of lung cancer. In stage I, the cancer is only present in the lungs. In stage II, the cancer spreads into the lymph nodes. In stage III, the cancer spreads into the lymph nodes of the middle of the chest. In stage IV, the cancer spreads fully to both lungs or to another organ.
There are several symptoms associated with lung cancer in the patient’s chest. The most common symptom is intense coughing, usually occurring persistently or in a series. A similar symptom that may be present is coughing up blood. Other symptoms include a change in the color of the patient’s mucus, shortness of breath, difficulty with breathing and swallowing, and pain in the chest, shoulder, and/or back. There are also several symptoms that spread to the rest of the body. These include weight loss, fatigue, memory loss, bleeding, pain in the bones, fever, and general weakness.
Fortunately, there are many methods of treatment of lung cancer. These methods include chemotherapy, radiation therapy, and surgery. In chemotherapy, chemicals are injected into the body to kill actively dividing cells in all parts of the body. In radiation therapy, radiation is used to kill cancer cells and shrink tumors in one part of the body by preventing the cells to divide. Surgery is often used in the first two stages of lung cancer to remove the lobe of the lung that contains the tumor.
Although lung cancer is the leading cause of deaths from cancer in the United States, there remains a chance of survival for patients of it. The survival rate of patients with lung cancer localized in the lungs is 52.6%. Unfortunately, the survival rate of patients with lung cancer that has spread to other organs is only 3.5%. Because of these statistics, it is important for patients recently diagnosed with lung cancer to seek immediate treatment.
In order to prevent getting lung cancer in the first place, you must avoid smoking and breathing in secondhand smoke at all costs. Smoking and inhaling smoke are the top causes of lung cancer. You must also handle industrial substances like uranium, coal, and gasoline with caution by wearing face protection to avoid inhaling their fumes. Unfortunately, these industrial substances are also found in air pollution, which is hard to avoid. If you have tuberculosis, it can cause the lung tissue to scar. Another unavoidable cause of lung cancer is in genetic mutations that can be inherited from family. In general, you must heed all the potential causes of lung cancer in order to keep from getting it in the first place.
Body fat is made up of fat cells, or adipose cells. These cells are made of one or more fatty acids and a glycerol. In the form of triglycerides, fat cells store fat later converted into energy and used by the body when needed. Ovarian cancer is cancer in the ovaries, the female reproductive organs that reproduce eggs. There is no cure for cancer, but the cause of this cancer is also undiscovered. Although, the cause of the cancer is unknown, there are many factors that affect the development of ovarian cancer. If a woman gives birth early in life, it decreases her chance for the development of ovarian cancer. Woman who have a family with a history of ovarian or breast cancer are at high risk for being diagnosed with ovarian cancer. Older woman have a higher jeopardy for being diagnosed with ovarian cancer compared to younger people. “FABP4 is a member of the intracellular lipid-binding protein family that is predominantly expressed in adipose tissue, and plays an important role in maintaining glucose and lipid homeostasis” (BioMed Central Ltd 2011).
The omentum is made of fat cells and provides nutrients for the growth of ovarian cancer. Ovarian cancer cells feed on the fat cells and increase rapidly. Tumor cells are attracted to the protein signals released by the omentum. During an experiment, the attraction was reduced by 50% with the help of inhibitors. The cancer cells feed on the lipid of the fat cells and the entire omentum, an area made up of a large amount of fat cells, is replaced by cancerous cells. Fat cells are increasing the growth of cancer cells through the omentum and researchers believe that an area made up of large amount of fat cells may also be food for other cancers such as breast cancer.
Fatty acid binding protein (FABP4) may be a treatment and stop the spread of the cancer. Primary ovarian cancer tissue, which had spread to the omentum, was compared to cancer cells distant from the fat cells. The cancerous cells next to the omentum produced high levels of FABP4, while cancer cells distant from the fat cells did not produce FABP4. Cancer cells fed less on fat cells when FABP4 was reduced. The transfer of nutrients from fat cells to cancer cells decreased when FABP4 was restrained. Researchers now conclude that FABP4 can be an appropriate treatment and may stop the spread of ovarian cancer through the omentum.
The article, “Fat Cells in Abdomen Fuel Spread of Ovarian Cancer”, includes many things that are supported by clear evidence. For example in the article it describes that, “A large pad of fat cells that extends from the stomach and covers the intestines provides nutrients that promote the spread and growth of ovarian cancer” (Science Daily October 30, 2011). This statement is built upon the research done at the University of Chicago in the journal Nature Medicine. Nature Medicine was published October 30th, 2011, so the information is up to date and valid because it was based upon research done by a group of students. The article also includes, “This fatty tissue, which is extraordinarily rich in energy-dense lipids, acts as a launching pad and energy source for the likely lethal spread of ovarian cancer” (Science Daily October 30, 2011). This report was given by Ernst Lengyel, after experimenting. The article states, “The researchers performed a series of experiments to identify the role of these fat cells as major mediators of ovarian cancer metastasis” (Science Daily October 30, 2011). Although it is stated that many experiments took place, there is only one experiment about FABP4, a fatty acid binding protein, which is mentioned in the article. I am left wondering, what the other experiments were because they weren’t revealed in the article. In the article it explains that, ovarian cancer cells injected into the abdomen of healthy mice find their way to the omentum within 20 minutes (Science Daily October 30, 2011). According to my research, older woman are at higher risk for developing ovarian cancer. If this is the case, then isn’t the age of the mice a factor in the experiment? The article included that the mice were healthy, but failed to extinguish the age of the mice.
FABP4, a fatty acid binding protein, is mentioned in the article and may be a possible candidate for the treatment of ovarian cancer. In class, we learned about two types of proteins and a generic fatty acid. Proteins are made up of carbon, hydrogen, oxygen, and nitrogen. Proteins are needed by the body for growth and repair. A regulatory protein, uses enzymes to maintain homeostasis while, a structural protein keeps structure. Elastin and collagen are two structural proteins. The amount of elastin decreases as you get older. Structural proteins are found in the skin and bones. Proteins are made up of amino acids, which are “compounds with an amino acid group on one end and a carboxyl group on the other end” (Kenneth R. Miller and Joseph S. Levine 49). An amino group is two hydrogen bonded to a nitrogen. A carboxyl group is a carbon double bonded to a molecule of oxygen and single bonded to an oxygen, which is also bonded to hydrogen (OH). A peptide bond is the bond between two amino acids. It connects the carbon (C) of the carboxyl group to the nitrogen (N) of the amino group. Two amino acids together are called a dipeptide while, three or more bonds between amino acids is called a polypeptide. The amino acids are combined using hydrolysis, or the adding of H2O to break down a larger component. Dehydration Synthesis, the removal of H2O, is used to separate a dipeptide. A lipid molecule is made up of three fatty acids and one glycerol. There are three types of lipids. If there is only a single bond between carbons in the fatty acids it is known as a saturated lipid. An unsaturated lipid has one double or triple bond between the carbons of the fatty acids and a polyunsaturated lipid has one or more than one double or triple bond between the carbons in the fatty acids. A generic fatty acid is made up of carbons, hydrogen and oxygen.
A treatment for ovarian cancer and, other cancers that develop in environments where fat cells are plentiful, will be a huge benefit for those who have ovarian cancer. The treatment may help researchers find a cure for ovarian cancer and lead them to find the cure for many other cancers. There is no cure for cancer, but this treatment may give hope to those who are fighting with cancer. If the treatment using FABP4, is successful for people suffering for ovarian cancer, the amount of people, especially woman, with ovarian cancer will decrease greatly. This treatment may also help researchers find what’s causing ovarian cancer.
Ovarian cancer is cancer in the ovaries, the female reproductive organs that reproduce eggs. There is no cure for cancer, but the cause of this cancer is also undiscovered. Although, the cause of the cancer is unknown, there are many factors that affect the development of ovarian cancer
Ovarian cancer cells feed on the fat cells and increases rapidly and soon the fat cells are replaced by cancerous cells. Fatty acid binding protein (FABP4) may be a treatment and stop to the spread of the cancer. Researchers now conclude that FABP4 can be an appropriate treatment and may stop the spread of ovarian cancer through the omentum.
The article, “Fat Cells in Abdomen Fuel Spread of Ovarian Cancer”, includes many things that are supported by clear evidence and several things that are not. In class, we learned about two types of proteins and a generic fatty acid. Proteins are needed by the body for growth and repair while, a three fatty acids and one glycerol make up one lipid molecule.
If the treatment using FABP4, is successful for people suffering for ovarian cancer, the amount of people, especially woman, with ovarian cancer will decrease greatly.
In the year of 2018, researchers predict that 164,690 new cases and 29,430 deaths will arise from the most common type of male reproductive cancer (American Cancer Society [ACS], 2018). Reproductive cancers affect the organs that are responsible for reproduction in the human body. For males, this constitutes their organs; the testicles, prostate gland, and the penis (U.S. Department of Health and Human Services [HHS], 2017). So, what is the most common type of reproductive cancer in males? According to the Mayo Foundation, it is prostate cancer. Prostate cancer is defined as a cancer that originates from the prostate gland due to the uncontrollable growth of its cells (ACS, 2018). The function of the prostate gland is to produce seminal fluid which is a component of semen. Then during ejaculation, the prostate aids in the release of this seminal fluid into the urethra (Ashford, 2010).
While it is still unclear what specifically causes prostate cancer, researchers have identified multiple risk factors that contribute to the increased likelihood of contracting the disease. According to the ACS, as the age of males increase, the chance of having prostate cancer also increases (2018). Research has shown that it is uncommon for men below the age of 40 to develop prostate cancer. It isn’t until the age of 50 that the risk drastically increases. Another risk factor for prostate cancer is race. Studies have shown that African-American males are more likely to have prostate cancer than other races. Additionally, African-American males tend to have a more aggressive stage of the cancer and therefore two times more African-American males die as opposed to white males. The reason for this is unknown (ACS, 2018). Further research correlated family history as a risk factor for prostate cancer as well. Men who have a family member that had prostate cancer are at a higher risk. It was also was investigated that if male also had a family history of breast cancer, then this could also increase the risk of prostate cancer (Mayo Foundation for Medical Education and Research [MFMER], 2018).
In the early stages of any type of cancer, it can be difficult to ascertain whether symptoms are present. In the case of prostate cancer, this is no exception. A male may not have any signs or symptoms until the disease has progressed further to a more aggressive stage. At the later stages of prostate cancer however, men may experience symptoms such as difficulty urinating, discomfort in the pelvic region, or erectile dysfunction. Additionally, men may notice blood in their semen, a decrease in the force at which they urinate, or pain that originates from their bones (MFMER, 2018).
If a male presents any of the above signs and symptoms, a physician would conduct certain diagnostic tests to determine if they are in fact caused by cancer in the prostate gland. First a screening test, such as a Digital Rectal Exam (DRE) or Prostate-Specific Antigen (PSA) test may be performed. A DRE consists of a physician inserting a lubricated, gloved finger into the rectum of a male to palpitate the prostate gland which is located adjacent to the rectum. Any changes in the size, texture, or shape of the prostate gland would result in further diagnostic tests. On the other hand, the PSA test takes a sample of blood and screens it for the substance PSA which is naturally produced by the prostate gland. If there are abnormally high levels of PSA in the blood this indicates there is a problem with the prostate gland which could include cancer (MFMER, 2018). If any of the screening tests come back with abnormal results, additional testing would be recommended by the physician. One diagnostic test involves a lubricated small probe inserted into the rectum that releases sound waves which creates echoes in the prostate and turns them into black and white images on the computer. This technique is a transrectal ultrasound (TRUS). A physician could also biopsy the prostate by using TRUS and a hollow needle. The needle would obtain a small portion of the prostate to be examined by a lab for any cancerous cells (ACS, 2018).
After a male is diagnosed with prostate cancer, there are various treatment options. Physicians determine the best treatment option by first ascertaining a male’s overall health, if the cancer has spread throughout the body, as well as the benefits and side effects of the treatment in question. It is possible that the cancer found in the prostate gland is not an immediate risk to the individual and no treatment is needed. For men in this situation, their suggested treatment is active surveillance which entails regular check-ups to ensure the cancer has not progressed or spread. Another option for men with a low-grade stage of this cancer is radiation therapy. There are two types of radiation therapies; external beam radiation therapy (EBRT) or brachytherapy which occur internally. Either of these treatments beam radiation on the prostate gland. If the cancer returns after radiation therapy, another treatment option that physicians may want to attempt is cryotherapy. Cryotherapy involves inserting TRUS and several hollow needles into the rectum while the patient is under general anesthesia that omits extremely cold gases to freeze and kill the prostate cancer cells (ACS, 2018) On the other hand, if the cancer in the prostate gland is at an advanced stage, a prostatectomy can be recommended. A prostatectomy is the removal of the prostate gland. The prostate gland is an organ that is not essential for life and therefore it has the ability to be removed to hopefully rid the body of the cancerous cells that it contains. The prostate gland can be removed via robotically or by an incision in your abdomen. Other recommendations for advanced stages of prostate cancer are hormone therapy and chemotherapy. Hormone therapy, also known as androgen deprivation therapy, seeks to eliminate or decrease the amount of the androgen hormones. One of the functions of androgen is to help prostate cells to grow and so by reducing the numbers of androgens in the body this may help reduce the cancer cells from multiplying.
In the state of Nebraska, males diagnosed with prostate cancer can be treated at Nebraska Hematology Oncology (NHO). The physician who specializes in the male reproductive tract, known as a urologist normally is the one to diagnose and treat the patients with prostate cancer. At NHO, there are a wide range of treatment options including biopsy, surgery, cryotherapy, and hormone therapy. Another provider in Nebraska that provides radiation therapy for prostate cancer is Radiation Oncology at Village Point up in the Omaha. Additionally, a center located up in Omaha that is geared towards cancer treatment is the Fred and Buffett Cancer Center. While a multitude of cancers can be treated here, prostate cancer is an area of focus for this center. They have a multidisciplinary team of surgeons, oncologists, and other specialists that can aid in treating prostate cancer.
More than 90% of of cancer related mortality is caused by metastasis. To develop new therapeutic strategies it is vital to understand the initiation and progression of metastasis. To identify and isolate metastasis initiating tumour-cells scientists developed a fluorescence-activated cell sorting (FACS)-based array. There are two types of metastasis-cells: metastasis-cells from low-burden cells and metastasis-cells from high-burden cells. After being transplanted, low-burden metastasis-cells showed that they have a considerable amount of tumour initiating ability and could differentiate to produce luminal-like cancer cells. When low-burden metastatic cells progress to high-burden metastasis cells they get an increased proliferation and MYC expression. This can be weakened with the use of inhibitors. This all supports a hierarchical model in which metastasis is initiated by stem-like cells, and can progress from low-burden to high-burden metastasis cells. The human breast contains two kinds of epithelial lineages: the basal/myoepithelial which contains stem-cells, and the luminal lineage which contains progenitor cells and mature cells.
The scientists used breast tissue from the mammoplasty of three individuals. With the use of numerous statistical analysis they concluded that basal/myoepithelial and luminal lineage is different for everyone.They focused in this experiment on a particular subtype, because this subtype is the most aggressive and there is no suitable treatment for it. The patient-derived xenograft maintained the same properties in the mice as in the patients and because of this it was suitable for the studies of human metastasis. To isolate the metastasis cells from the patient derived xenograft mice they developed a new FACS based array. With this they were able to detect metastatic cells in 70% of the patient-derived xenograft peripheral tissue from the mice. The mice were analyzed when their tumours reached 20-25 mm in diameter. The growth kinetics was consistent within each model. Although the tumour of every animal had about the same diameter they all had great variation in metastatic burden.
The scientists also found out that PCA plots for mice with low burden metastasis cells were further away from the tumour they derived from than high burden metastasis cells. Other experiments also showed that low burden metastasis cells liked to form clusters with each other while high-burden metastasis cells liked to form clusters with primary tumour cells. The scientists found out that low burden metastasis conserved their basal/myoepithelial signatures. They had expressed higher levels of 22 basal/myoepithelial genes and expressed lower levels of 7 luminal genes. By focusing on clustering only the metastasis cells the scientists discovered incredible heterogeneity in differentiation, which correlated with metastatic burden. Akin to the mammary gland metastatic cells organized into two different clusters, where the low-burden cells were the most basal/stem-like and the high-burden cells were the most luminal-like. The scientists concluded the same conclusion with lung metastatic cells. Which means that it is a conserved phenomenon in each model. There were some differences between gene expression of lung metastatic cells of different models, but they were not enough to cluster metastatic cells separately by patient derived xenograft models.
In order to investigate heterogeneity at protein level scientists performed immunostaining for a basal and luminal gene. Tumour cells found in micrometastatic from low-burden tissues had a high percentage for the basal gene and luminal gene and tissues from high-burden tissues had a high percentage for the luminal gene and were heterogeneous for the basal gene. This suggest that differentiation status correlates with metastatic burden in protein-level.By means of single cell analyses scientists discovered that in the low-burden metastatic cells had high levels of pluripotency genes. These genes suggest that they are exploited embryonic programs for self-renewal and maintenance. Low-burden metastatic cells also expressed higher levels of typical EMT-markers, except for an EMT-marker which was typically found in normal basal/stem cells. All these findings are consistent with previous reports which show that EMT promotes stemness in mammary gland, and suggest that low-burden metastatic cells utilize an EMT-program to make dissemination easier.
Further studies also revealed that genes involved in the DNA damage response, chromatin modification, differentiation, apoptosis and the cell cycle were differentially expressed in low-burden metastatic cells.Because of the heterogeneity in metastatic cells scientist wondered if stem-like cells directly give rise to luminal-like cells, or if the luminal cells are originated from founder-cells. After an experiment the scientist concluded that luminal-like cells can derive from cells that disseminate at the early stages of primary tumour growth. To test the growth and differentiation capacity of stem like metastatic cells, scientists transplanted low-burden metastatic cells into mammary glands. Interestingly 2 of 4 transplanted cells produced large tumour, while primary tumour cells never produced tumours, even at 100 fold high numbers. This is consistent with the previous reports which showed that PDX tumours are more efficiently increased as fragments than dissociated cells.
After single cell analyses scientists concluded that low burden-metastatic cells have high tumour initiating capabilities, and that they can give rise to luminal-like tumour cells. This supports the hypothesis that stem-like metastatic cells give rise to luminal metastatic cells. Another interesting question the scientists had was is stem-like cells were present in tumour cells, or if they evolve after interaction with their microenvironment. After a test the scientists concluded that primary tumours contain a rare subpopulation of stem-like cells, and that the percentage correlates with metastatic potential. Afterwards scientists wanted to know if enrichment of this stem-like signature in primary tumours may be predictive of distant metastasis in human patient data sets. After an analyses the scientists found that 16 of 55 genes associated with stem-like metastatic cells were significantly prognostic. Previous work has shown that metastatic cells in different organs display specific gene expression signatures. Supervised clustering by the targeted organ has shown that metastatic cells in brain, bone marrow and peripheral blood have differences in gene expression patterns. Brain metastatic cells are the most different.
CTC’s are very important for diagnosis. Most CTCs and bone marrow DTCs clustered with intermediate metastatic cells. This might have been because the cells were from animals with intermediate burden. However, 16.7% and 10.7%, showed a more basal/stem-like signature, which sugges that these stem-like cells may represent the initial metastatic seeder cells.Scientists also observed a shift towards a more quickly increased signature which have been correlated with increased metastatic burden. Low-burden metastatic cells expressed higher levels of rest and dormancy-associated genes. Higher-burden metastatic cells appeared to enter the cell cycle, expressing lower levels of quiescence and dormancy-associated genes and higher levels of cell-cycle-promoting genes. Scientists also discovered primary tumour cells (22.2%) with this less-proliferative signature.
These discoveries inspired scientists to test if blocking this switch from inactivity into the cell cycle could stop metastatic progression. Since scientists detected high levels of both MYC and CDK2 in more advanced stage metastatic cells , the scientists chose to test a CDK inhibitor that has been shown to end apoptosis in high MYC-expressing cancer cells. The scientists came up with a hypothesis that apoptosis would be started in metastatic cells progressing into proliferation, since they appear to upregulate MYC. After testing this on mice the scientists found that by looking in high resolution at gene expression in single metastatic cells, scientists have uncovered an previously unrealized range in differentiation and gene expression linking to the metastatic stage ,and demonstrate that this approach can ease the recognition of new potential drug targets with efficiency against metastatic disease.METHODSTo begin with the analysis the researchers first gathered the cell lines and the xenografts of the tumour tissues, which were grown and acquired according to standard and ethical protocols.
The xenografts were divided into tumour fragments and propagated into the breasts of the mice. When the tumours became palpable, that’s when the tumours were measured weekly to oversee their growth rate. The tumour fragments were stored by freezing them in liquid nitrogen. All animals from which xenografts were derived were euthanized at the end, when the tumours had grown to about 20 to 25 mm in size. During the resection experiment, tumours were usually removed when they reached the size of about 10 to 12 mm. The animals on which resection was performed were brought back to their colony and were warranted to grow metastases for 8 weeks, during which lung tissue was gathered and analysed by fluorescence-activated cell sorting (FACS) for human cells.In order to measure the functional activity of metastatic cells, orthotopic transplant experiments were performed on the animals. Particular metastatic cells in the lymph nodes, as well as particular tumour cells from matched animals, were segregated by FACS and combined from various animals. The sorted cells were formed into pellets and inserted into a media. Diluted versions of these were inserted into the breasts of 3.5-week-old mice and grafts were taken after 4.5 months when the primary tumours became 20 mm in size.
After this began the dinaciclib treatment experiments, which were administered when the tumours became palpable. The dinaciclib was primed and acquired according to protocol. The mice were randomly appointed to treatments when the tumour cells were transplanted and analysed with the help of the single-blind design. In total, 49 animals were injected with the treatment three times a week. Animals were measured twice a week to report primary tumour growth. The mice were euthanized at the end of the treatment or earlier if the tumour reached 20 mm in diameter. Animals which developed unfavourable effects were ruled out of the study. The microarray gene expression values were calculated using some form of statistics program. Plasma membrane genes expressed greatly on all of the 15 tumour sample xenografts. The 12 initial patient tumour samples were ranked from highest to lowest expression. The predicted value of every one of the 55 genes characteristics of low-burden metastatic cells was worked out by Kaplan–Meier analysis.
All solid tissues and the brain were dissociated for FACS. The tissues were cut up and placed in culture medium. They were then broken down for 45 min at 37 °C. The suspensions that arose were then inserted into a solution of DNase for 3 min at room temperature, after which they were washed and dissociated again. After this peripheral blood, supernatant and bone marrow were collected, cells were pelleted for 5 min and leftover erythrocytes in peripheral blood, lung and tumour samples were lysed for 5 min at room temperature. All unused samples were directly filtered and stored by freezing them in liquid nitrogen. The tissues from the reduction mammoplasty were washed three to five times, cut into small fragments and digested overnight in a solution. The digested fragments were then pelleted for 3 min, frozen and then stored in liquid nitrogen. The antibodies for several particular human antigens were bought commercially. Both human and mouse antibodies were stained. After 15 min of lying on ice, the stained cells were washed to get rid of excess antibodies and put back into the medium. The cells were then flow sorted and analysed. Dead cells were eliminated and contaminating human or mouse haematopoietic and endothelial cells were excluded. The complete tissue sample in the single-cell multiplex qPCR experiments was run through the flow cytometer. A steady number of live cells were found in the tissues of all of the animals.
The results of mice which deviated by more than one standard deviation were excluded from the study. Single-cell gene-expression experiments were carried out with microfluid chips. Single cells were sorted using FACS into distinctive wells. The experiments were done according to protocol. Each well was prefilled with a solution. After the sorting process, the PCR plated were frozen and or placed into the thermocycler to go through the process of combined reverse transcription and target-specific amplification. Exonuclease reaction solution was subsequently added to remove unincorporated primers. Each well was then diluted. A bit from each sample was then dropped into a separate plate and mixed with another solution. Individual primer assay mixes were made in yet another plate. The chips were primed before the samples and assays were mixed into them. The chips were then evaluated thoroughly. All of the single-cell PCR data were analysed using a statistical analysis software. In its entirety, 268 mammary cells from reduction mammoplasties as well as 441 metastatic and 523 primary tumour cells from the xenografts of the mice were analysed.
The results of the analyses were developed into Ct values, which were then further generated into statistical language.In regular mammary cell experiments, the Ct values were standardized by deducting the average value of the basal/stem-cell population per gene and per array. In the mice xenograft experiments, the Ct values were standardized by deducting the average primary tumour expression per gene as well as the average value of the basal/stem-cell population per gene and per array. Low quality samples were found and withdrawn from additional analysis.Various statistical tests were performed in order to determine gene expression differences between earlier established populations. For regular mammary cell experiments, a threefold comparison was initiated between basal/stem, luminal, and luminal progenitor cells. This generated an array of 49 differentially expressed genes. To find out of which population each gene is an aspect of, pair-wise tests were executed. When comparing metastatic cell experiments to that of primary tumour cells, only the pair-wise tests were executed.
Threefold comparisons were executed to compare lung metastatic cells from the three xenografts from the mice and fivefold comparisons were executed to compare metastatic cells from each tissue. These analyses were done with a variety of statistical programs. In order to find passages which were represented in a greater fashion in the set of significantly differentially expressed genes that they would have been by just chance, an enrichment analysis of Biological Process gene ontology terms was executed using several statistical programs. For both histological analysis and immunofluorescent analysis, the tissues were suspended overnight in paraformaldehyde and processed paraffin embedding. The tissues were stained with haematoxylin and eosin for histological analysis. In order to commence the immunofluorescent analysis, the tissues were stained using immunofluorescent staining. The immunofluorescent staining was used upon lung tissues with low and high metastatic burden.On the sections with paraffin-embedded tissue immunostaining was carried out by using a citrate buffer and heating the sections in a pressure cooker for 8 min. Several human genes were stained with the help of a three-step method. First, the primary antibodies were incubated overnight, which was then followed by one-hour incubations along with detecting antibodies after which a fluorescent binding biotin was added.
MYC and phospho-histones were found by following a two-step method, in which the overnight staining of antibodies was followed up by a one-hour incubation along with detecting antibodies. The number of positive nuclei was counted for tumour, high burden, and low burden cells, after which the significance was calculated by a statistical analysis software.