Week 10 & 11: Cancer Biology & Management Flashcards
Discuss the etiology of cancer including genetic, epigenetic, environmental, and lifestyle factors.
Environment-lifestyle behaviors and genetic factors contribute to the formation of cancers. Cancer is driven by genetic alterations and changes in epigenetic regulation. The development of cancer and its progression involve the tissue microenvironment or stroma, where infiltrating immune cells cause chronic inflammation, creating a permissive tumor-progressing environment. Factors that influence cancer risk include:
*Detoxifying enzymes
*DNA repair genes
*Immune/inflammatory systems
*Cell’s immediate environment
*Metabolic/hormonal factors
Explain the pathophysiologic processes of cancer that affect cells and contrast with normal cellular functioning
Cancer is a complex disease, and the microenvironment of a tumor is a heterogeneous mixture of cells, both cancerous and benign. Cancer is a disease of cumulative genetic changes during aging. Genetic changes involve mutational and epigenetic mechanisms. Mutation means an alteration in the DNA sequence affected expression or function of a gene. Mutations include point mutations, chromosome translocations, and gene amplification. Epigenetic effects can alter gene expression indirectly and include DNA methylation, histone acetylation, or altered expression of non-coding RNA. DNA mutations “drive” the progression of cancer, but not all mutations in cancer contribute to the malignant phenotype - some are just random events, called passenger mutations. After a critical number of mutations has occurred, a cell becomes cancerous.
What is a benign neoplasm?
Benign tumors are usually encapsulated with connective tissue and contain fairly well-differentiated cells and well-organized surrounding supportive tissue called stroma. They retain recognizable normal tissue structure and do not invade beyond their capsule, nor do they spread to regional lymph nodes or distant locations. Benign tumors are generally named according to the tissues from which they arise with the suffix “-oma”, which indicates a tumor or mass. Benign tumors can still become extremely large and, depending on their location in the body, can cause morbidity or be life-threatening. Some tumors initially described as benign can progress to cancer and then are referred to as malignant tumors.
List & describe the 10 hallmarks of cancer.
- Avoiding Immune Destruction: active inflammation pre-disposes individuals to cancer but also stimulates a wound-healing response that supports tumor growth. Also includes the immune surveillance hypothesis and the immunotherapy hypothesis.
- Evading growth suppressors: evasion of the genes responsible for inducing and suppressing growth
- Enabling replicative immortality: cancer cells can activate telomerase, leading to continued division.
- Tumor-promoting inflammation
- Activating invasion and metastasis
- Genomic instability (mutator phenotype): involves the mutation of genes involved in regulating cell growth
- Inducing angiogenesis: advanced cancers can secrete angiogenic factors to facilitate feeding of the tumor.
- Resisting cell death: apoptotic pathways are dysregulated in most cancers
- Deregulating cellular energetics
- Sustaining proliferative signaling: involves uncontrolled cellular proliferation where cytoplasmic components of the receptors activate intracellular signaling pathways that induce/activate regulatory factors that affect DNA synthesis, entrance into the cell cycle, and changes in expression of other genes related to cell metabolism for optimal growth
Discuss and differentiate between local invasion versus distant spread of cancer.
Metastasis is the spread of cancer cells from the site of the original tumor to distant tissues and organs through the body. Metastasis is a defining characteristic of cancer and is the main cause of death from cancer. The process of metastases requires cancer cells to leave their primary site, circulate in the bloodstream, withstand pressure in the blood vessels, thrive in the new cellular surroundings, and escape “destruction” by immune cells. Unfortunately, communications with the tumor microenvironment allow invading cancer cells to conquer stromal challenges, settle, and colonize. Characteristics are driven by genetics and epigenetic changes within the tumor cell itself and its microenvironment. Invasion involves evolution of new abilities in cancer cells that facilitate metastasis (i.e., EMT) and starts with tumor extension and then eventually migration away from the primary tumor.
What is cancer?
A disease in which some of the body’s cells begin to divide without stopping and spread into surrounding tissues. The term cancer comes from the Latin translation of the Greek word for crab, karkinoma.
What is a tumor?
Describes new growth or neoplasm. Neoplasms result from an abnormal growth following uncontrolled proliferation serving no physiologic purpose. Not all tumors or neoplasms, however, are cancer.
What is a malignant neoplasm?
Malignant tumors are distinguished from benign tumors by more rapid growth rates and specific microscopic alterations, including **loss of differentiation ** and absence of normal tissue organization.
One of the microscopic hallmarks of cancer cells is anaplasia, the loss of cellular differentiation. Malignant cells are also pleomorphic, with marked variability of size and shape. They often have large, darkly stained nuclei, and mitotic cells are common. Malignant tumors may have a substantial amount of stroma, but it is disorganized, with loss of normal tissue structure.
The most important and most deadly characteristic of malignant tumors is their ability to spread far beyond the tissue of origin, a process known as metastasis.
Unlike benign tumors, which are named related to the tissue or origin, cancers generally are named according to the cell type from which they originate. Cancers arising in epithelial tissue are called carcinomas, and if they arise from ductal or glandular structures they are named adenocarcinomas. Cancers arising from mesenchymal tissue (including connective tissue, muscle, and bone) usually have the suffix sarcoma. Cancers of lymphatic tissue are called lymphomas, whereas cancers of blood-forming cells are called leukemias.
Discuss the impact of tobacco and cigarette smoking in cancer development.
The main inducer of both lung cancer and chronic obstructive pulmonary disease (COPD) is cigarette smoke. Cigarette smoke induces an inflammatory response and causes an increase in reactive oxygen species (ROS), causing oxidative stress. Oxidative stress is a risk factor for many diseases because it can alter many cellular proteins. A combination of immune inflammatory signals and epigenetic events may increase the risk for individuals with COPD developing lung cancer.
Discuss the impact of diet on cancer development.
*Nutrition may influence the regulation of the normal cell cycle, which ensures correct DNA replication. *However, dietary components can also act directly as mutagens or interfere with the elimination of mutagens. Xenobiotics that include toxic, mutagenic, and carcinogenic chemicals are found in many foods and medications.
Certain enzymes (glutathione-S-transferases GSH) are “enzyme housekeepers” that play essential roles in the metabolism of environmental carcinogens and reactive oxygen species (ROS). Individuals who have absent or reduced levels of these protective enzymes may be at higher risk for cancers because of a decreased capacity to effectively neutralize carcinogens by metabolic transformation into less toxic forms.
Additionally, DNA requires methylation to properly regulate gene expression. Diets lacking in the dietary donors may struggle with methylation. Primary donors include: folate, choline, and B vitamins. Altered micro-ribonucleic acid (miRNA) may additionally predispose an individual to cancer. Consuming kiwi fruits, cooked carrots, or supplemental coenzyme Q10 may improve DNA repair.
Discuss the impact of obesity on cancer development.
Obesity has been linked mechanistically to both an increase in cancer risk and cancer progression. Because tumor growth is regulated by interactions between tumor cells and their tissue microenvironment, stromal compartments rich in adipose tissue can promote the development of tumor cells. During cancer progression, cancer-associated adipocytes (CAAs) undergo both structural and functional alterations that create a favorable micro-environment for increased cellular invasiveness and aggression. Cancer cells alter adipocytes through lipolysis and dilapidation leading to CAAs that produce abnormal amounts of adipocyte-derived cytokines (increased leptin and decreased adiponectin), as well as release inflammatory cytokines and protease enzymes. The adipokine leptin increases inflammation and is associated with stromal effects that promote cancer cell proliferation, metabolism, angiogenesis, and invasion. In obese individuals, changes in glucose and lipid metabolism are found in the tumor microenvironment as well as systemically. Obesity causes dysfunctional adipose tissue to produce increased levels of insulin-like growth factor (IGF-1), sex-hormones, and adipokines that contribute to obesity-related metabolic changes such as insulin resistance, hyperglycemia, dyslipidemia, hypoxia, and chronic inflammation. As described previously, inflammation is an important contributor to both tumor initiation and progression. Excess adipose tissue can become reservoirs of lipophilic organochlorines and other fat-seeking toxic agents that can enhance proinflammatory mediators, which attract macrophages and cancer-associated fibroblasts, all of which are tumor-promoters. Additionally, the associated insulin resistance and hypoxia can trigger compensatory angiogenesis, thus providing an energy reservoir for any embedded cancer cells. Type 2 diabetes, elevated insulin levels, and altered insulin signaling pathways in obese individuals have been linked to cancer risk and progression as well as resistance to cancer therapies.
There are currently 13 cancers associated with overweight and obesity:
- Meningioma
- Adenocarcinoma
- Multiple myeloma
- Kidneys
- Uterus
- Ovaries
- Thyroid
- Breast
- Liver
- Gallbladder
- Upper stomach
- Pancreas
- Colon and rectum
Discuss the impact of alcohol consumption on cancer development.
Alcohol is classified by IARC as a human carcinogen and is known to increase circulating unbound hormones as well as obesity. Overall, there are strong data linking alcohol with cancers of the mouth, pharynx, larynx, esophagus, liver, colorectum, and breast (in both males and females). The evidence does not support any “safe limit” of intake. The deleterious effects come from the ethanol content and are not affected by the type of drink consumed. Acetaldehyde is the most toxic metabolite of alcohol and is the chief cause of alcohol-related carcinogenesis.
Discuss the impact of air pollution on cancer development.
Air pollution is specifically linked to lung cancer and can be caused by outdoor or indoor pollution. Outdoor pollution includes particle pollution which causes pulmonary inflammation, oxidative stress, and oxidation of DNA, which can result in nonfatal heart attacks, irregular heartbeat, and decreasing lung function. Indoor pollution includes cigarette smoke and radon and is considered worse than outdoor pollution.
Discuss the impact of radiation on cancer development.
Ionizing radiation is a potent DNA-damaging agent causing cross-linking, nucleotide base damage, and single-or double-strand DNA breaks thus disrupting cellular regulation processes leading to carcinogenesis. from x-ray machines, radioisotopes, and other radioactive sources can result in acute leukemias, increased frequencies of thyroid and breast carcinomas, lung, stomach, colon, esophageal, and urinary tract cancers. Radiation enters cells and randomly deposits energy in tissue resulting in oncogene activation, tumor-suppressor genes deactivation, chromosomal aberrations, and DNA damage, as well as cell transformation.
Non-ionizing radiation includes electromagnetic radiation and differs from IR in the way it acts on materials like air, water, and living tissue. NIR includes the spectrum of UV, visible light, infrared, microwave, radio frequency, and extremely low frequency. EMR originating in the UV part of the spectrum and above can interact with material leading to the direct ionization of atoms and molecules and is considered to pose a health risk.
UV radiation is principally caused by sunlight and results in basal cell carcinoma, squamous cell carcinoma, and melanoma.
Lastly, electromagnetic radiation (EMR) is energy in the form on transverse magnetic and electric waves and includes microwaves, radar, mobile and cellular telephones/base stations, appliances, etc.
Discuss the impact of infections on cancer development.
Among the more notable infections contributing to new cancer cases are Helicobacter pylori, human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV). H.pylori contributes to about 75% of stomach cancers. HPV, HBV, and HCV infect the liver and together account for the preponderance of liver cancer cases. EBV is linked to nasopharyngeal carcinoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, EBV-associated malignant B-cell lymphoma, other lymphomas, and gastric adenocarcinoma. HPV accounts for more than half of the total infection-attributable cancers in women worldwide, resulting in cervical, as well as other genital cancers. HPV types 16 and 18 cause the majority of cancers. HPV infects epithelial cells and mutations lead to cancer.
Human herpesvirus type 8 is linked to Kaposi sarcoma, and human T-cell lymphotropic virus type 1 is linked to leukemia and lymphoma.
Discuss the impact of physical activity on cancer development.
Regular exercise is reported to decrease the risk of breast cancer, colon cancer (men), and endometrial cancer independent of weight changes. Several biologic mechanisms have been proposed to account for the protective effect of exercise against many forms of cancer, including:
- Decreasing insulin and IGF levels
- Decreasing obesity
-Increasing free radical scavenger systems
- Altering inflammatory mediators
- Decreasing levels of circulating unbound sex hormones and metabolic hormones
- Improving immune function
- Decreasing oncogenes
-Enhancing cytochrome P-450 and thereby modifying carcinogen activation
- Increasing gut motility and excretion of carcinogens
- Increasing antitumor effects from the release of myokines or proteins from contracting muscles
After a cancer diagnosis, physical activity is associated with improved cancer-specific and overall survival with early-stage breast, prostate, and colorectal cancers.
Define Mutation
Mutations means alteration in the DNA sequence affecting expression or function of a gene and includes:
- Point mutations: which are small-scale changes in DNA that involve the alteration of one or more nucleotide base pairs resulting in sometimes profound effects on the activity of resultant proteins
- Chromosome translocations: large changes in chromosome structure in which a piece of one chromosome is translocated to another chromosome
- Gene amplification: is the result of repeated duplication of a region of a chromosome; instead of the normal two copies of a gene, tens or even hundreds of copies are present
Define clonal proliferation.
Also known as clonal expansion, is when cancer cells have selective advantage as their progeny accumulate faster than their non-mutated neighbors
Define malignant transformation.
The process by which a normal cell becomes a cancer cell, and is directed by progressive accumulation of genetic changes that alter the basic nature of the cell and drive it to malignancy.
Discuss sustained proliferative signaling.
The first and prime hallmark of cancer is uncontrolled cellular proliferation. Normal cells generally only enter proliferative phases in response to growth factors that bind to specific receptors on the cell surface. The cytoplasmic components of the receptors send signaling molecules that activate intracellular pathways leading to induction/activation of regulatory factors affecting DNA synthesis, entrance into the cell cycle, and changes in expression of other genes related to cell metabolism for optimal growth. One example is initiation of proliferation by epidermal growth factor (EGF). EGF binds and cross-links two EGF receptors on the cell surface
Discuss evading growth suppressors.
Uncontrolled cancer cell proliferation also is related to inactivation of tumor-suppressor genes. Tumor-suppressor genes normally regulate the cell cycle, inhibit proliferation resulting from growth signals, stop cell division when cells are damaged, and prevent mutations. Therefore, they also have been referred to as anti-oncogenes. Whereas oncogenes are activated in cancers, tumor suppressors must be inactivated to allow cancer to occur. A single genetic event can activate an oncogene because it can act in a dominant manner in the cell. However, we have two copies of each tumor-suppressor gene, one from each parent. Both copies must be inactivated; thus, two mutations are necessary (homozygous mutations, also called loss of heterozygosity).
The most mutated gene in many human cancers is the p53 tumor-suppressor gene (TP53). TP53 missense mutations are the most common mutation in human cancers. The protein p53 acts as a tumor suppressor, which means it regulates cell division by restricting cells from growing and dividing too fast or in an uncontrolled way; thus, it is called the guardian of the genome.
Discuss genomic instability.
Genomic instability is an increased tendency of alterations - mutability - in the genome during the life cycle of cells. Inherited and acquired mutations in caretaker genes that protect the integrity of the genome and DNA repair increase the level of genomic instability and risk for developing cancer.
Three key genetic mechanisms have a role in human carcinogenesis:
- Activation of proto-oncogenes, resulting in hyperactivity of growth-related gene products (called oncogenes)
- Mutation of genes, resulting in the loss or inactivity of gene products that would normally inhibit growth (called tumor-suppressor genes)
- Mutation of genes, resulting in over-expression of products that prevent normal cell death or apoptosis, thus allowing continued growth of tumors
Discuss oncogenes & tumor-suppressor genes.
The genes that encode components of receptor-mediated pathways designed to regulate normal cellular proliferation are collectively called proto-oncogenes. Cancerous cells characteristically express mutated or overexpressed proto-oncogenes, which are called oncogenes.
Oncogenes are independent of normal regulatory mechanisms; thus, the cell is driven into a state of unregulated expression of proliferation signals and uncontrolled cell growth.
Tumor-suppressor genes encode proteins that, in their normal state, negatively regulate proliferation. They are also referred to as anti-oncogenes.
Discuss tumor induced angiogenesis.
An important component of wound healing is the process of establishing new blood vessels within the tissue undergoing repair (called neovascularization or angiogenesis). Access to a blood supply also is obligatory for the growth and spread of cancer. Without a blood supply to deliver oxygen and nutrients, growth of a tumor is limited to about a millimeter in diameter. Angiogenic factors and angiogenic inhibitors typically control development of new vessels. In cancerous tumors, several mechanisms increase and maintain secretion of angiogenic factors by the cancer cells and prevent release of angiogenic inhibitors. Hypoxia-inducible factor-1α (HIF-1α), an oxygen-sensitive transcription factor, is a primary regulator of angiogenesis in normal tissue; HIF-1α is stabilized under hypoxic conditions and induces expression of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Inactivation of tumor-suppressor genes or increased expression of oncogenes (e.g., HER2) leads to increased expression of HIF-1α–regulated angiogenic factors and increased vascularization. The vessels formed within tumors differ from those in healthy tissue. They originate from endothelial sprouting from existing capillaries and irregular branching, rather than regular branching seen in healthy tissue. The interendothelial cell contact is less tight, so the vessels are more porous and prone to hemorrhage and allow passage of tumor cells into the vascular system.
Discuss telomeres & replication immortality.
A hallmark of cancer cells is their immortality; they seem to have an unlimited life span and will continue to divide for years under appropriate laboratory conditions. Most normal cells are not immortal and can divide only a limited number of times (known as the Hayflick limit) before they either enter senescence (cease dividing) or enter crisis (apoptosis) and die. One major block to unlimited cell division (i.e., immortality) is the size of a specialized structure called the telomere. Telomeres are protective ends, or caps, of repeating hexanucleotides (six nucleotide units) on each chromosome and are placed and maintained by a specialized enzyme called telomerase. telomerase is usually active only in germ cells (in ovaries and testes) and in stem cells. All other cells of the body lack telomerase activity. Thus, when non–germ cells begin to proliferate abnormally, their telomere caps shorten with each cell division. Short telomeres usually signal the cell to cease cell division. If the telomeres become critically small, the chromosomes become unstable and fragment, and the cells die. Cancer cells are very heterogeneous, and many cells die as the cancer develops. When they reach a critical age, most cancer cells reactivate telomerase to restore and maintain their telomeres, thereby allowing continuous division. Telomerase not only maintains telomere length, but it also affects DNA replication, cellular apoptosis, tumorigenesis, and resistance to therapy by cancer cells, including those of breast and cervical origin. Cancer cells move closer to immortality by upregulating telomerase and downregulating tumor suppressor genes.
Discuss how cancers avoid cell death.
Programmed cell death (apoptosis) is a mechanism by which individual cells can self-destruct under conditions of tissue remodeling or as a protection against aberrant cell growth that may lead to malignancy. Two pathways may trigger apoptosis. The intrinsic pathway (mitochondrial pathway) monitors cellular stress. Cellular stress may include DNA damage, genomic instability, aberrant proliferation, loss of adhesion to ECM or to adjacent cells, and other causes and characteristics of abnormal cellular physiology. The extrinsic pathway is activated through a plasma membrane receptor complex linked to intracellular activators of apoptosis (known as the death receptor). Apoptotic pathways are dysregulated in most cancers. Most commonly, loss-of-function mutations to the TP53 gene suppress activation of apoptosis during DNA damage.
Discuss resistance to destruction in cancer.
The inflammatory response contributes to the onset of cancer, and cancer is a cause of chronic systemic and local inflammation. Tumors can manipulate the inflammatory process in their local tumor microenvironment to benefit tumor progression and spread. Cancer also causes systemic perturbations in both innate and adaptive immune processes that reduce the body’s ability to fight the cancer. Active inflammation predisposes a person to cancer by stimulating a wound-healing response that includes proliferation and new blood vessel growth - angiogenesis, which is part of the normal inflammatory response. Some organs are more susceptible than others and that includes those that undergo the cell cycle frequently (i.e., GI, pancreas, thyroid, prostate, urinary bladder, skin).
