Patho Ch 12 to 14 Summary Review

Additional context

This document delves into the fundamental characteristics and terminology of cancer, a complex group of diseases with profound global health implications. It builds upon decades of research into cellular biology and genetics, particularly the understanding of mutations and epigenetic modifications that drive uncontrolled cell proliferation. The work aligns with established concepts such as the hallmarks of cancer, which describe the core capabilities acquired by malignant cells, including sustained growth, evasion of apoptosis, and the ability to invade and metastasize. By defining the distinctions between benign and malignant neoplasms and detailing the genetic underpinnings and microenvironmental influences on tumor development, this summary provides a foundational understanding crucial for further investigation into targeted therapies and diagnostic advancements.

Cancer Terminology and Characteristics

1. Cancer is a leading cause of suffering and death in the developed world. Intensive research is defining this collection of related complex diseases. It is a disease in which abnormal cells divide uncontrollably, invade, and metastasize to other tissues. A tumor is a new growth, or neoplasm.

2. Cancer is more than 100 diseases, each caused by a specific and often unique age-related accumulation of genetic and epigenetic alterations. Environment, behavior, and heredity modify the risk of developing cancer and the response to treatment.

3. Benign tumors are usually encapsulated and well differentiated with well-organized stroma and do not spread to distant locations. They are named for the tissues from which they arise. Benign tumors are noncancerous.

4. Malignant tumors are cancerous. Compared with benign tumors, malignant tumors have more rapid growth rates, specific microscopic alterations (anaplasia, or loss of differentiation, and pleomorphism, or variability in size and shape), absence of normal tissue organization, and no capsule. They invade blood vessels and lymphatics and have distant metastases. The stroma is disorganized with loss of normal tissue structure.

5. Cancers are named for the cell type from which they originate. Carcinomas arise from epithelial tissue, lymphomas are cancers of lymphatic tissue, and leukemias are cancers of blood-forming cells.

b. Carcinoma in situ (C.I.S) refers to noninvasive epithelial tumors or glandular or squamous cell origin. These early-stage cancers are localized to the epithelium and have not penetrated the local basement membrane.

The Biology of Cancer Cells

1. Cancer is a complex disease, and the microenvironment of a tumor is a heterogenous mixture of cells, both cancerous and benign.

2. Tumor initiation is dependent on mutational and epigenetic changes and characteristics of the microenvironment. Tumor progression is governed further by more genetic mutations, epigenetic alterations, and changing microenvironment.

3. Genetic changes include small and large D.N.A mutations that alter genes, chromosomes, and non-coding R.N.A's, as well as epigenetic changes because of altered chemical modifications of D.N.A and histones.

4. Driver mutations “drive” the progression of cancer. Passenger mutations are random events that do not contribute to the malignant phenotype. After a critical number of driver mutations, the cell becomes cancerous.

Definition

Telomerase: An enzyme that maintains the length of telomeres (protective caps at the ends of chromosomes), which is typically reactivated in cancer cells to achieve replicative immortality.

5. Mutations activate growth-promotion pathways, block antigrowth signals, prevent apoptosis, stimulate telomerase and new blood vessel growth, and allow tissue invasion and distant metastasis.

6. Each cancer cell may develop its own set of mutations resulting in a genomically heterogeneous mixture of cancer cells with subsets that have accumulated more and more mutations. Intratumoral genetic heterogeneity or diversity arises from ongoing proliferation and mutation and can lead to therapy resistance.

7. The processes that occur during the development of cancer are analogous to wound healing. The proliferation of cancer cells and enlargement of the tumor elicit synthesis of proinflammatory mediators by the cancer cells and adjacent nonmalignant cells.

8. Like wound healing, mediators recruit inflammatory/immune cells and cells normally associated with tissue repair. These cells form the stroma (tumor microenvironment) that surrounds and infiltrates the tumor.

Definition

Genomic instability: An increased tendency for mutations to occur in the genome during cell division, often due to defects in D.N.A repair or chromosome segregation.

9. Hallmarks of cancer that are primarily genomic alterations include sustained proliferative signaling, evading growth suppression, genomic instability, and replicative immortality.

10. Other hallmarks secondary to genomic change include induction of angiogenesis and reprogramming energy metabolism. A third group, tumor resistance to destruction by the host's protective mechanisms, include resistance to apoptotic cell death, tumor-promoting inflammation, avoiding immune destruction, and the last hallmark activating invasion and metastasis.

11. Many of the hallmarks of cancer are consequences of cancer-stromal interactions.

2 Definitions

Definition 1: Oncogenes: Mutated or overexpressed proto-oncogenes that promote uncontrolled cell proliferation independently of normal regulatory signals.

Definition 2: Genetic translocation: A chromosomal abnormality where a segment of one chromosome breaks off and attaches to another chromosome, potentially leading to altered gene expression or function.

12. Normal cells only enter proliferative phases in response to growth factors. Cancerous cells characteristically express mutated or overexpressed proto-oncogenes, referred to as oncogenes, which are independent of normal regulatory mechanisms and signal uncontrolled sustained proliferation. Genetic translocation alters the myk proto-oncogene and hyperproduction of myk protein drives proliferation and blocks differentiation.

13. Some oncogenes, such as ras, result from point mutations. Other oncogenes can result from genetic translocations. Genetic translocation alters the myk proto-oncogene and hyperproduction of myk protein drives proliferation and blocks differentiation.

14. Translocation can cause excess and inappropriate production of a proliferation factor, such as with Burkitt lymphoma. Translocations can also lead to production of novel proteins with growth-promoting properties, as is seen with the Philadelphia chromosome in chronic myeloid leukemias (C.M.L's).

Definition

Tumor-suppressor genes: Genes that normally regulate the cell cycle and prevent uncontrolled proliferation; their inactivation by mutation is required for cancer development.

15. Tumor-suppressor genes normally regulate cell cycle, but they must be inactivated in cancer cells by mutations to each allele, one from each parent.

16. The most mutated gene in a wide variety of human cancers is the p53 tumor-suppressor gene (T.P.5.3). The protein, p53 acts as a tumor suppressor, thus it regulates cell division by restricting cells from growing and dividing too fast or in an uncontrolled way the “guardian of the genome.” The p53 is in the nucleus and attaches directly to D.N.A. If D.N.A is damaged by such agents or stressors as toxic chemicals, radiation or ultraviolet radiation and others the protein plays a critical role in whether D.N.A is repaired, or the damaged cells undergo apoptosis. If the D.N.A can be repaired, p53 activates other genes or caretaker genes, for repair. If the D.N.A cannot be repaired, p53 prevents the cell from dividing and signals it to undergo apoptosis.

Definition

Senescence: A state of permanent cell cycle arrest, which can act as a tumor suppressor mechanism but can also, under certain conditions, promote cancer development.

17. The p53 controls initiation of senescence (cease dividing), which has been shown to exhibit both a tumor suppressor and an oncogenic effect.

Definition

Senescence-associated secretory phenotype (sasp): A characteristic secretion profile of senescent cells that includes inflammatory mediators and proteases, which can alter the cellular environment and promote cancer.

18. Cellular senescence can promote cancer development by altering the cellular environment through a senescence-associated secretory phenotype (sasp).

19. The retinoblastoma gene1 (R.B.1), a tumor suppressor gene is mutated in childhood retinoblastoma and in some lung, breast, bladder, bone cancers, leukemias, and melanoma.

20. Genomic instability refers to an increased tendency of mutations in the genome during the life cycle of cells. Genomic instability in inherited and acquired mutations in caretaker genes increases the level of genomic instability and risk for developing cancer. Genomic instability may result from increased epigenetic silencing or modulation of gene function.

Definition

micro R.N.A's (m.i.R.N.A's or miRs): Small non-coding R.N.A molecules that regulate gene expression post-transcriptionally, and can play roles in cancer development and progression.

21. Changes in gene regulation can affect entire networks of signaling, not just single genes. Gene expression networks can be regulated by changes in micro R.N.A's (m.i.R.N.A's or miRs) and other non-coding R.N.A's (n.c.R.N.A's).

Definition

Oncomirs: micro R.N.A's that promote cancer pathways and contribute to the development and progression of tumors.

22. Oncomirs or oncogenic m.i.R.N.A's promote multiple cancer pathways.

Definition

Chromosome instability (C.I.N): A type of genomic instability characterized by a high rate of chromosome loss, gain, or rearrangement during cell division.

23. In addition to specific gene mutations and abnormal epigenetic silencing, chromosome instability (C.I.N) also appears to be increased in malignant cells, resulting in a high rate of chromosome loss, as well as loss of heterozygosity and chromosome amplification.

24. Cancer cells are immortal. wnen tney reacn a critical age, most cancer cells reactivate telomerase to restore and maintain their telomeres, thereby allowing cancer cells to divide repeatedly. Cancer cells move closer to immortality by upregulating telomerase and downregulating tumor suppressor genes.

25. Telomerase also affects D.N.A replication, cellular apoptosis, tumorigenesis, and resistance to therapy.

26. Cancer stem cells (C.S.C's) are a subpopulation of tumor cells that have replication immortality. They arise from tissue resident stem cells or develop from transformed differentiated cells. Transformation from differentiated cells into C.S.C's occurs through the activation of oncogenes, inactivation of tumor suppressor genes, and re-expression of telomerase.

27. C.S.C's can change their appearance and function in response to the tumor microenvironment such that they drive cancer progression, serving as the cellular seeds for tumor growth, metastases, and disease recurrence.

28. Access to the vascular system is essential for tumor growth. Cancerous tumors maintain secretion of angiogenic factors and prevent the release of angiogenic inhibitors, which stimulates new blood vessel growth (called neovascularization or angiogenesis).

29. The vessels formed within tumors originate from endothelial sprouting from existing capillaries and irregular branching, rather than regular branching seen in healthy tissue. The vessels are also more porous and prone to hemorrhage and allow passage of tumor cells into the vascular system.

30. Another form of angiogenesis in tumors is called vasculogenic mimicry. Tumor cells form tubular structures like blood vessels that contain erythrocytes. These tubular tissues can attach to blood vessels to form a vascular network.

31. Cancer cells can reprogram energy metabolism. The successful cancer cell divides rapidly, with the consequent requirement for the building blocks of new cells, such as A.T.P. Many cancer genes encourage aerobic glycolysis instead of oxidative phosphorylation, which allows for a more efficient production of molecular building blocks needed for rapid growth.

32. Oncogenes can drive metabolic reprogramming, enabling cancer cells to (1) maintain deregulated proliferation, (2) withstand challenges associated with oxygen and nutrient limitations, (3) maintain a dedifferentiated state with associated alterations in gene expression, and corrupt the surrounding microenvironment to assist tumor growth and dissemination.

33. In cancer, defects in the intrinsic or extrinsic cell death pathways, or both, provide resistance to apoptotic cell death.

34. 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.

35. Cancer also causes systemic perturbations in both innate and adaptive immune processes that reduce the body's ability to fight the cancer.

36. Some conditions of chronic inflammation increase the risk of developing cancer. A prime example is the association between gastric cancer and infection with Helicobacter pylori.

37. One of the key cells that promotes tumor survival is the tumor-associated macrophage (T.A.M). Most tumors have large numbers of T.A.M's, whose presence may correlate with a worse prognosis.

38. Cancer-associated fibroblasts (C.A.F's) contribute greatly to cancer progression, local spread, and metastasis. Studies have documented how the number of C.A.F's, or their function is linked to outcomes. The heterogeneity of C.A.F's, their functions and possible changeability, pose a challenge for the field,

39. Several viruses are associated with cancer and include human papillomavirus (H.P.V), Epstein-Barr virus (E.B.V; also known as H.H.V.4), Kaposi sarcoma herpesvirus (K.S.H.V; also known as H.H.V.8), hepatitis B and C viruses (H.B.V, H.C.V), and Merkel cell polyomavirus. Cancer of the cervix and hepatocellular carcinoma account for approximately 80% of virus-linked cancer cases.

40. Although some cancer cells do express tumor-specific antigens that can be recognized by the immune system, most cancer cells do not, and those that do, most often present antigens that are undetectable by the immune system. Cancer cells have developed multiple mechanisms to evade the immune system. As cancer cells proliferate, clonal development of immune-resistant variants arises.

41. Immune cells have surface molecules whose purpose is to activate (co-stimulatory factors) or suppress (co-inhibitory factors) immune responses to antigens. Co-inhibitory molecules are often called immune checkpoints. Cancer cells may suppress T cells by binding to immune checkpoints, causing the lymphocyte to turn off its attack. Checkpoint inhibitors are a group of immunotherapy drugs that block this interaction, thus reactivating the immune cell to attack the tumor.

42. The role of the immune system in protecting against cancer has been clearly documented against oncogenic viruses. Antibodies induced by vaccines against oncogenic viruses, such as human papillomavirus (H.P.V) and hepatitis B virus (H.B.V), protect against initial infection and development of cervical and liver tumors, respectively.

Activating Invasion and Metastasis

1. New paradigms in the study of metastasis have identified molecular underpinnings of the dissemination process.

2. Improved understanding of how the invading tumor cell interacts with other proteins and cells has elucidated new biological principles by which metastatic cells regulate their mobility and plasticity.

3. Communications with the tumor microenvironment allows 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.

4. Hanahan and Weinberg identify that “activating invasion and metastasis” is a hallmark of cancer. Understanding these mechanisms of the metastatic process is critical to develop successful treatment interventions.

5. Dissemination of cancer cells leads the initial steps of the invasion-metastasis cascade. Chromosomal instability becomes the “trigger” causing constant and continuous errors in chromosome segregation during mitosis.

6. Investigators suggest that the nature of the primary seeding cancer cell determines the various and different metastatic properties aligned with growth and response to therapy.

7. Seeding may require the joint action of a cluster of tumor cells moving together.

8. E.M.T is the developmental (transdifferentiation) process whereby transformed epithelial cells lose their cell polarity and cell-cell adhesion, and gain the ability to invade, resist stress, and disseminate. The triggers for E.M.T in cancer cells include hypoxia, metabolic stressors, and matrix stiffness.

9. Research in pancreatic and lung cancers reveals that E.M.T might not be essential for metastasis, but it does contribute to chemoresistance.

10. Although the initiation of metastasis may involve E.M.T, mesenchymal-epithelial transition (met) is necessary for metastatic progression.

11. Various metastatic cells possess different genetic and epigenetic or phenotypic changes, which differentially drive tumor progression, metastasis, and drug resistance.

12. Genetic expression is affected by oxygen homeostasis in the tumor microenvironment.

13. Hypoxia-inducible factors (H.I.F's) enable cancer cells to adapt to their environment by modulating angiogenesis, E.M.T, invasion, metastasis, and energy metabolism.

14. Metastatic characteristics are transferred through extracellular vesicle exchange. Extracellular vesicles called exosomes transfer invasion-promoting factors from the primary tumor, such as m.i.R.N.A's, to tumorigenic cancer cells. Exosomes secrete E.M.T inducers that stimulate E.M.T progression in host epithelial cells, enabling them to invade and metastasize.

15. E.C.M altered by exosomes exhibits increased stromal cell proliferation, cancer cell migration and survival, and tumor cell resistance to apoptotic signals. These changes plus effects of growth factors and chemokines, lead to the formation of a new microenvironment for cancer cells, immune cells, and other stromal elements, known as the P.M.N.

16. Age-related physical changes in the E.C.M inhibit or promote tumor cell motility, invasion, and metastasis.

17. The circadian clock controls a wide spectrum of processes in cellular physiology through metabolic and gene expression pathways. It has been associated with cancer initiation and progression.

18. Diet has been shown to impact cancer metastasis. Some of these dietary effects may be related to changes in the microbiome. Other effects are more direct. For example, asparagine is an important promoter of metastasis, and researchers have found that removing asparagine from the diet of mice reduced breast cancer metastases.

19. In cancer, remodeling of the interstitial E.C.M causes a broad range of biophysical and biochemical changes affecting cell signaling, E.C.M stiffness, cell migration, and tumor progression.

20. Binding of cells to the basement membrane is critical for establishing cell polarity, and crucial for several developmental processes and maintenance of tissue homeostasis. Remodeling of the basement membrane is required for cancer cells to invade stromal tissue and become a malignant tumor.

21. Tumor-derived activation factors induce the differentiation of stromal cells towards C.A.F's, which function as myofibroblasts and remodel the E.C.M to support tumor growth. E.C.M is complex, and numerous specific cells and matrikines engage in invasion and metastasis.

22. The immune environment surrounding the tumor plays a significant role in dictating the metastatic potential of the disseminating cells.

23. Intravasation, or the movement of cancer cells through the lumen of the vasculature, is mediated both actively and passively depending on the tumor type, microenvironment, and vasculature.

24. Importantly, integrins regulate the colonization process by easing anchorage-independent survival of circulating tumor cells (C.T.C's). Metastatic cells use E-cadherin in metastatic sites to detach, disseminate, and seed, thereby promoting metastatic cell survival and block apoptosis.

25. Interactions between C.T.C's and the microenvironmental components of circulation determine survival and the ability of C.T.C's to extravasate in distant places. The dissemination of C.T.C's is supported by very close association with activated platelets and macrophages. The leukocytes that showed the greatest interaction were neutrophils, their role in metastasis is not yet clear. The complex interaction between cancer cells and leukocytes promotes metastasis because metastatic cells possess sugar on their cell surface that binds to galectin-3. Galectin-3 increases the ability of cells to colonize by interacting with mobilized leukocytes.

26. In mouse models, blocking of I.L-6 and I.L-8 receptors decreased metastasis at lymph nodes, lungs, and liver.

27. C.T.C's use, exploit, and survive in the bloodstream during metastasis and cause distant metastases also through the lymphatic circulation. C.T.C characterization identifies the molecular aspects of metastatic tumors.

28. Cell-free D.N.A (c.f.D.N.A) identifies the heterogeneity of C.T.C's in those with high counts of C.T.C's. Liquid biopsy of C.T.C's and /or c.f.D.N.A in the bloodstream may have the potential to increase understanding of metastasis. A photoacoustic method for direct use in persons with melanoma enables the detection of very low numbers of C.T.C's in vivo and their destruction with laser pulses. Additionally, D.N.A methylation profiles more clearly identify tumor phenotypes among C.T.C clusters than from single cells.

29. Critical in the metastatic process is the ability of C.T.C's to adhere and extravasate through endothelial cells and colonize the premetastatic neesh (P.M.N).

30. Extravasation is a complex process. It involves ligand-receptor interactions, chemokines, and circulating non-tumor cells. Integrins are once again very important.

They help to determine the location for extravasation and colonization. Cancer cells induce programmed necrosis of endothelial cells, driving metastatic cells to extravasate.

31. Most cancers metastasize to specific target organs, a process called metastatic organotropism. The host microenvironment and the ensuing adaptive process that invading cancer cells undergo play a role in extravasation and colonization at specific sites.

32. Formation of the P.M.N, where the tumor cells colonize and grow, depends on signaling from various tumor secreted derived factors and bone marrow-derived factors. Exosomes play a significant role. Formation of a vascular network is critical for optimal colonization.

33. Vascular mimicry where tumors create their own channels for fluid transport drives the ability of some breast cancer cells to contribute to distant metastases through the expression of serpine2 and S.L.P.I.

34. Colonizing cancer cells use signaling from neuronal pathways for growth and adjustment to new sites.

35. Cancer dormancy is a rest phase in cancer progression that occurs during the primary tumor formation phase or after invasion into secondary sites. Metastatic dormancy occurs because of the delayed adjustment of disseminating cells to their secondary niches or sites affecting single invading cells or cancer clusters after circulation. These dormant cancer cells (D.C.C's) are rarely detectable with current diagnostic approaches. Much evidence supports the notion that extracellular signal-regulated kinase (e.r.k) activation has a determinant role in whether cancer cells will proliferate or enter the phase of dormancy. Reawakening D.C.C's could be a critical factor for cancer development from chronic inflammation. Chronic inflammation can induce epigenetic alterations and D.N.A mutations in tumor suppressor genes, thus promoting carcinogenesis. Existence of D.C.C's has led to the emergence of therapy resistance because the cells may resume growth, increasing the risk of unleashing lethal metastatic outbreaks even after a long latency period of months to years.

36. In the last decade a significant number of metastasis suppressors have been identified, most notably m.i.R.N.A's. Metastatic cancers may be approached through a biomarker-driven strategy that validates single-agent or combination of agents depending fully on the molecular makeup of individual tumors.

37. A priority is the importance of lifestyle and diagnostic factors in reducing cancer mortality. Obesity is becoming a critical etiologic driver of cancer and initiation of metastasis. Worldwide, other preventable risk factors are a significant cause of cancer.

Clinical Manifestations of Cancer

1. Paraneoplastic syndromes are rare disorders with complex clinical manifestations that are triggered by a cancer but are not caused by direct local effects of the tumor mass. Malignant cells do not cause symptoms related to metastasis, but they generate autoantibodies, cytokines, hormones, or peptides that affect may organ systems.

2. Common side effects of cancer and cancer therapy include anemia, bone density loss, cachexia, cardiac and pulmonary damage, fatigue, gastrointestinal issues. hair loss and skin conditions, infection, infertility, leukopenia and thrombocytopenia, lymphedema, and pain.

3. Anemia associated with cancer usually occurs because of malnutrition, chronic bleeding and resultant iron deficiency, chemotherapy, radiation, and malignancies in the blood-forming organs.

4. Cachexia is a complex metabolic syndrome associated with basic illness and is characterized by the loss of muscle with or without loss of fat mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and loss of lean body mass with or without wasting of adipose tissue. Multiple mechanisms are involved in the development and progression of cachexia including anorexia, decreased secretion of anabolic hormones, inflammation, decreased physical activity, and altered metabolic responses with abnormalities in protein, lipid, and carbohydrate metabolism. Profoundly altered are both appetite-stimulating and appetite-suppressing brain pathways.

5. Fatigue is the most frequently reported symptom of cancer and cancer treatment.

6. The gastrointestinal tract relies on rapidly growing cells to provide an absorptive surface for nutrients. Both chemotherapy and radiation therapy may cause decreased cell turnover, thereby leading to oral ulcers (stomatitis), malabsorption, and diarrhea.

7. Alopecia (hair loss) results from chemotherapy effects on hair follicles. Alopecia is usually temporary, although hair may initially regrow with a different texture. Not all chemotherapeutic agents cause alopecia. Decreased renewal rates of the epidermal layers in the skin may lead to skin breakdown and dryness, altering the normal barrier protection against infection.

8. Infection is a significant cause of complications and death. Immune suppression, lymphopenia, and granulocytopenia may result from the underlying cancer or secondary to treatment increasing the risk of serious microbial infections.

9. Leukopenia and thrombocytopenia are usually a result of chemotherapy (which is toxic to bone marrow) or radiation (which kills circulating leukocytes). Thrombocytopenia is a major cause of hemorrhage in people with cancer.

10. Pain is generally associated with the late stages of cancer. It can be caused by pressure, obstruction, invasion of a structure sensitive to pain, stretching, tissue destruction, and inflammation.

Diagnosis and Staging of Cancer

1. Tumor tissue is obtained to establish a definitive diagnosis and correctly classify the disease. Once tissue is obtained, it is examined microscopically by the pathologist for the histologic hallmarks of cancer. Cancer classification is established by a variety of tests including immunohistochemical stains, flow cytometry, electron microscopy, chromosome analysis, and genetic studies.

2. Tumor staging involves the size of the tumor, the degree to which it has locally invaded, and the extent to which it has spread. One common scheme for staging is the T (tumor spread), N (node involvement), and M (metastasis) system.

3. Tumor markers are substances (i.e., hormones, enzymes, genes, antigens, antibodies) found in cancer cells and in blood, spinal fluid, or urine. They are used to screen and identify individuals at high risk for cancer, to help diagnose specific types of tumors, and to follow the clinical course of cancer. To date, no tumor marker has proven satisfactory to screen populations of healthy individuals for cancer.

4. Cancer is treated routinely with surgery, radiation therapy, chemotherapy, and combinations of these modalities. Immunotherapy has now established itself as a pillar of cancer care from the metastatic stage to the adjuvant and neoadjuvant settings in many cancer types. Cancer therapy is rapidly evolving, and genetic analysis may help determine appropriate therapies.

5. Surgical therapy is used for nonmetastatic disease (in which cure is possible by removing the tumor) and as a palliative measure to alleviate symptoms.

6. Ionizing radiation causes cell damage; therefore, the goal of radiation therapy is to damage the tumor without causing excessive toxicity or damage to no diseased structures.

7. The theoretic basis of chemotherapy is the vulnerability of tumor cells in various stages of the cell cycle. Modern chemotherapy uses combinations of drugs with different targets and different toxicities.

8. Increasing evidence of most approved cancer drugs, including tyrosine kinase inhibitors (T.K.I's), systemic cytotoxic therapies (chemotherapy) and antibody-drug conjugates (A.D.C's), reveals they do not have a durable impact with metastatic disease often because of therapeutic resistance.

9. Induction chemotherapy seeks to cause shrinkage or disappearance of tumors. Adjuvant chemotherapy is given after surgical excision of a cancer with the goal of eliminating micrometastases. Neoadjuvant chemotherapy is given before localized (surgical or radiation) treatment of a cancer to shrink a cancer so that surgery may spare more normal tissue.

10. The recent discovery of T cell immune checkpoints, such as cytotoxic T lymphocyte antigen 4 (C.T.L.A-4) and programmed cell death 1 (P.D-1), moved the field of immuno-oncology into its current era. The challenge is harnessing immune signals that maintain a fine balance between immune surveillance against foreign pathogens or abnormal cells and autoimmunity. Immunotherapy attempts to modify the immune system from a cancer-protective state to a destructive condition. Dedicated scientists and clinicians are mobilized to achieve a higher response rate without increasing autoimmunity.

Ch 13

Genetics, Epigenetics, and Tissue

1. Cancer arises from a complicated and interacting web of multiple etiologies, with fewer than 10% of all cases stemming from inherited germline factors. All cancer develops when the healthy genes with which we are born lose their ability to enhance D.N.A repair, direct proteins to induce cell death at appropriate times, or promote beneficial cell signaling. Avoiding high-risk behaviors and exposure to carcinogens can prevent many types of cancers.

2. Risk factors for cancer include lifestyle behaviors (smoking, alcohol intake, diet), lack of physical exercise and obesity, certain infections, environmental factors (exposure to sunlight, ionizing or non-ionizing radiation as well as drinking water contaminants), occupational exposure to carcinogens, and certain medications or common contaminants in pharmaceuticals that can turn on malignant processes through chromosome rearrangements or other processes.

3. Cancers are caused by interactions between environmental-lifestyle factors and inherited or acquired genetic/epigenetic factors. Contributing factors include weaker immune systems, variations in detoxifying enzymes or D.N.A repair genes, differences in hormone levels, and metabolic factors such as disordered glucose and lipid metabolism.

4. Cancer-causing factors are influenced by the surrounding microenvironment or stroma. Once malignant phenotypes have developed, complex interactions occur between the tumor, the surrounding stroma, and cells of the immune and inflammatory systems.

5. Globally, cancer is reported to remain a major cause of morbidity and mortality in the coming decades in both developed and developing regions.

6. For the first time, female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer in the world, primarily because of increases in low-and middle-income countries. Lung cancer is the most commonly diagnosed cancer in men, and for both sexes it is the leading cause of cancer death in the world. Prostate cancer is the second most common cancer in men. Other common cancers worldwide arise from the gastrointestinal tract including colorectum, stomach, and liver cancers. Despite these increases in incidence, overall U.S cancer death rates have decreased 31% since 1991, especially due to a decline in lung cancer deaths. The rate of decline in cancer-rated mortality has slowed for prostate, breast, and colorectal cancer since 2018.

7. Increased Generational Risk (G.R) is evident in trends in cancer not related to smoking or diagnostic ascertainment, with persons born after 1940 experiencing up to twice as much cancer as those born earlier. Explanations for increases in specific subtypes of non-smoking related cancer need to be sought.

8. Race, ethnicity, and social class are major determinants of the risk of developing and dying of cancer around the world, reflecting largely socioeconomic factors that affect access to care, good nutrition, workplace, and environmental exposures.

In yoo-tuh-roh and Early Life Conditions

1. Emerging data suggest prenatal and early life events influence later susceptibility to cancer and other chronic diseases.

2. Developmental plasticity is the degree to which an organism's development is contingent on its environment. Plasticity refers to the ability of genes to organize physiologically or structurally in response to environmental conditions during fetal development.

3. The developmental origins hypothesis suggests that nutrition and other environmental factors affect cellular pathways during gestation, enabling a single genotype to affect a broad range of adult phenotypes. Maternal nutrition, as well as environment factors, are proposed as significant biological influences.

4. Undernutrition in yoo-tuh-roh is linked to increased heart disease, metabolic disorders, and possibly breast cancer decades later. Deficiencies that occur in the first trimester are far more influential than those that take place in the last trimester in affecting disease outcome in adulthood.

Environmental-Lifestyle Factors

Tobacco Use

1. Cigarette smoking is carcinogenic and the most important known avoidable cause of cancer that is controlled by individual behaviors. Tobacco smoking causes cancer in more than 15 organ sites, and exposure to secondhand smoke and parental smoking causes cancer in children and in other nonsmokers. The risk is greatest in those who begin to smoke when young and continue throughout life. Smoking is, however, a pandemic affecting all ages.

2. Worldwide, tobacco use causes more than 7 million deaths per year.

3. Environmental tobacco smoke (i.e., secondhand smoke) is a cause of stroke; increases the risk of death in people with cancer and cancer survivors as well as those with macular degeneration, tuberculosis, ectopic pregnancy, and diabetes mellitus. Secondhand smoke exposure increases inflammation, impairs immunity, and is a cause of rheumatoid arthritis.

4. Smoking tobacco is linked to cancers of the lung, upper aerodigestive tract, stomach, lower urinary tract, kidney, pancreas, cervix, uterus, and myeloid leukemia. Recently added to the list of smoking-related cancers are liver and colorectal cancer. Smoking causes even more deaths from respiratory, vascular, and other diseases than from cancer.

5. Cigar or pipe smoking is related to cancers of the oral cavity, oropharynx, hypopharynx, larynx, esophagus, and lung. Pipe smokers have an increased risk of cancers of lung, lip, throat, esophagus, larynx, pancreas, and colon and rectum.

6. Electronic cigarettes can contain harmful, highly-addictive, and potentially cancer-causing substances and have been extensively marketed to young teens and are targeted by public health authorities as potential gateways to tobacco smoking.

Diet

1. The influence of diet on cancer development is complicated. Cancer risks in older adults may depend as much or more on diet in early life as on current eating practices.

2. Nutrigenomics is the study of the effects of nutrition on the phenotypic variability of individuals based on genomic differences.

3. Nutrition, obesity, alcohol consumption, and physical activity all influence risks for cancer development and can interact synergistically.

4. As a tool for preventive medicine aimed at reducing disease, dietary recommendations, such as the Mediterranean diet, are becoming more widespread.

5. The importance of diet has been illustrated by data showing changes in cancer risk among migrants that move from countries with low-cancer risk to those with high-cancer risk countries. With geographic migration, particularly with the adoption of the Western diet, cancer risks approximate those of the new region within a generation.

6. Bioactive components have a profound effect on differentiation, potentially including differentiation of cancer stem cells. Intake of a broad range of specific food compounds may suppress cancer stem renewal.

7. A variety of food compounds may serve as antioxidants and influence cell signaling and D.N.A repair.

8. Xenobiotics can be toxic, mutagenic, and carcinogenic chemicals that humans are constantly exposed to. The body has several immunological systems for counteracting these effects, including enhanced production of Natural Killer cells and other anticarcinogens. Many foods enhance the efficiency and degree of detoxification of xenobiotics and thus serve a protective role in metabolizing carcinogens.

9. Diets high in red meat or processed meat may lead to increased risks of colorectal cancer. Meats containing nitrites, nitrates, or other preservatives can leave residues in the colon that cause D.N.A damage.

10. Obesity is an epidemic in both developed and developing countries. Obesity is a form of poor nutrition or overnutrition, that impacts energy balance, cancer risk, cancer recurrence, and survival.

11. Obesity is a risk factor for 13 cancers: liver, advanced prostate, ovarian, gallbladder, kidney, colorectal, esophageal, breast (postmenopausal), pancreatic, endometrial, meningioma, multiple myeloma, and stomach.

12. Understanding the mechanisms of obesity-associated cancer risks is evolving and varies by type of tumor and distribution of body fat. Emerging data point to three main factors: insulin-insulin-like growth factor (I.G.F-1) axis, (2) sex hormones, and adipokines.

13. Metabolic changes in adipose tissue from obesity result in several alterations and include insulin resistance, hyperglycemia, dyslipidemia, hypoxia, and chronic inflammation. Tumor growth is regulated by interactions between tumor cells and their tissue microenvironment, so stromal compartments that are rich in adipose tissue can promote the development of tumor cells.

14. Alcohol is classified as a human carcinogen. Strong data link alcohol with cancers of the mouth, pharynx, larynx, esophagus, liver, colorectum, and breast.

15. Evidence does not show any safe limit of alcohol and the health effects are from ethanol regardless of the type of drink.

16. Alcohol-related carcinogenesis involves acetaldehyde, reactive oxygen species (R.O.S), pro-carcinogen activation, cellular regeneration, nutritional deficiencies, and enzyme and metabolic dysfunction.

17. Physical activity, independent of weight changes, reduces the risk for breast cancer, colon cancer (in men), and endometrial cancer.

18. Biologic mechanisms for the protective effects of physical activity include decreasing insulin and I.G.F levels, decreasing obesity, increasing free radical scavenger systems, altering inflammatory mediators, decreasing levels of circulating unbound sex hormones and metabolic normones, improving immune function, decreasing oncogenes, enhancing cytochrome P-450 activity (thus modifying carcinogen activation), increasing gut motility, and increasing release of myokines (proteins from contracting muscles with antitumor effects).

19. Many unanswered questions remain regarding frequency of exercise, intensity, and duration.

20. Recent data encourage 150 minutes of moderate-intensity aerobic or 75 minutes of vigorous-intensity aerobic physical activity each week for adults. Children and adolescents should get at least 60 minutes of physical activity daily.

Air Pollution

1. Air pollution, indoor and outdoor, is the leading environmental cause of death worldwide. Long-term exposure to air pollution increases mortality and morbidity and shortens life expectancy from cardiovascular, respiratory disease, and lung cancer.

2. There is a significant association between increased rates of lung cancer and exposure to particulate matter, a mixture of small particles and liquid droplets. Primary particles are emitted directly from a source, for example, construction sites, unpaved roads, fields, or smokestacks. Secondary particles are emitted from power plants, industries, and automobiles.

3. Diesel exhaust is carcinogenic and causes lung cancer. Acute exposure to diesel exhaust that contains particles is linked to lung, throat, and eye irritations; asthma attacks; and myocardial ischemia.

4. The mechanisms of adverse effects of particulate matter include (1) oxidative stress, R.O.S generation, D.N.A oxidative damage, (4) mutagenicity, (5) stimulation of proinflammatory factors, and induction of senescence.

5. Fine particle pollution also is linked to (1) premature death in people with heart or lung disease, (2) nonfatal heart attacks, (3) irregular heartbeat, (4) aggravated asthma, (5) decreased lung function, and respiratory symptoms.

6. Indoor air pollution is generally considered worse than outdoor pollution. Sources of indoor air pollution include tobacco smoke, heating and cooking combustion sources, radon, and coal use.

Ionizing Radiation

1. Much of the knowledge of the effects of ionizing radiation on human cancer has come from Hiroshima and Nagasaki atomic bomb exposures, particularly the Life Span Study. Other evidence is from exposure to radiation for medical reasons, underground miners, and other occupational exposures. Human exposure includes emissions from the environment, x-rays, C.T scans, radioisotopes, and other radioactive sources.

2. Atomic bomb exposures in Japan caused acute leukemias and increased frequencies of thyroid, breast, lung, stomach, colon, esophageal, and brain, urinary tract cancers and multiple myeloma.

3. Excess relative risks (E.R.R's) for radiation-induced cancers at a given age are much higher for individuals exposed during childhood or over age 40.

4. The bimodal age distribution of radiation-induced cancer risk means that radiation exposure in early ages is related to initiation of cancer processes, whereas exposure in later ages is associated with promotion of pre-existing premalignant cells.

5. Other health risks from radiation include cardiovascular and neurodegenerative effects and somatic mutations that may contribute to other diseases. These effects may manifest years after radiation exposure.

6. There is concern about the increased I.R exposure from medical procedures, particularly C.T scans.

7. I.R is a potent mutagen and carcinogen; it can penetrate cells and tissues and deposit energy in tissues at random in the form of ionizations.

8. I.R affects D.N.A by causing cross-linking, nucleotide base damage, and single-and double-strand D.N.A breaks. Disrupted cellular regulation processes can lead to carcinogenesis. The double-strand break is considered the hallmark lesion associated with I.R.

9. It is now known that radiation may induce genomic instability to the progeny of the directly irradiated cells over many generations of cell divisions and can affect so-called bystander cells. Investigators are studying genomic instability as it may contribute to secondary cancers.

10. The risks from low-dose radiation are difficult to calculate because they require monitoring of large populations, and this is not regularly done.

Ultraviolet Radiation

1. Ultraviolet (U.V) radiation comes from sunlight, electric lights, black lights, and tanning lamps. Most of the U.V radiation received on earth is U.V.A and some U.V.B. U.V.A radiation is weaker than U.V.B, but U.V.A penetrates more deeply into the skin and is more constant throughout the year despite the weather.

2. The incidence of basal cell carcinoma (B.C.C) and squamous cell carcinoma (S.C.C) is strongly correlated with lifetime sunlight exposure. Intense intermittent recreational sun exposure has been associated with melanoma and B.C.C. Chronic occupational sun exposure has been associated with S.C.C. Tanning bed use has been associated with an increased risk of B.C.C, especially in women.

3. Skin cancer risk factors include cumulative sun exposure (the additive effects of intermittent sun exposure, chronic sun exposure, or both), ionizing radiation, chronic arsenic ingestion and other chemical exposures, immunosuppression, and genetic factors.

4. The pathogenesis of nonmelanoma skin cancers involves specific gene mutations, epigenetic alterations, oxidative stress, inflammation, and reduced immune surveillance.

Electromagnetic Radiation

1. E.M.R occurs in the form of magnetic and electric fields, and varies with power, frequency, polarity, information content, wave form, and other variables. Exposures are widespread and growing exponentially in recent years, especially for toddlers and young children who must rely on wireless devices for education during the pandemic. Wireless telecommunication devices (e.g., cell phones, wireless laptops, smart meters) are the most common sources of radiofrequency electromagnetic radiation (RF-E.M.R).

2. Competing priorities (convenience, financial interest, and health necessity) may make a consensus on the risk/benefit ratio of E.M.R difficult to achieve.

3. Low-frequency electromagnetic fields (E.M.F's) and higher-frequency E.M.F's (from cellphones and other wireless transmitting devices) have been classified as possible carcinogens by several expert groups, including the E.P.A, and the I.A.R.C of the W.H.O in 2011. More recently, experimental and epidemiological evidence amassed in the past decade reveal that E.M.F/R.F constitutes a known cause of cancer in humans.

4. Importantly, exposures from numerous wireless transmitting devices have expanded dramatically, especially for children.

5. Children are a main concern since the effects of exposure may be compounded because of their increased vulnerability to both I.R and N.I.R/E.M.F radiation, their immature immune systems, thinner skulls, and immature nervous systems and their longer use of cell phones and other wireless transmitting devices throughout their lifetimes.

6. Exposures from the proposed 5 G system are poorly understood but involve beam-forming from closely placed antennas that will also send and receive 3 G and 4 G frequencies to connect billions of existing devices; the millions of new antennas that are needed for this system have not been adequately evaluated for impacts on public health or the environment according to the U.S Government Accountability Office, 2020, and the European Union, 2020.

Infection, Sexual and Reproductive Behavior

1. Infection with certain viruses, bacteria, and parasites are an important contributor to cancer worldwide. The most notable infections implicated in new cancer cases include Epstein-Barr virus (E.B.V), Helicobacter pylori, hepatitis B and C viruses (H.B.V and H.C.V), and human papillomavirus (H.P.V).

2. H. pylori is the cause of about 75% of stomach cancers. E.B.V is linked to nasopharyngeal carcinoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, E.B.V-associated malignant B-cell lymphoma, other lymphomas, and gastric adenocarcinoma. H.B.V and H.C.V infect the liver and together account for the large majority of liver cancer cases.

3. H.P.V is the most common sexually transmitted virus in the United States and accounts for more than half of the total infection-attributable cancers in women worldwide. H.P.V types 16 and 18 are responsible for the majority of cancers. Persistence of infection with high-risk H.P.V is a prerequisite for the development of cervical intraepithelial neoplasia, lesions, and invasive cancer.

4. H.P.V infection has been identified as a definite carcinogen for several types of cancer: cervical, penis, vulvar, vaginal, anal, and some oropharyngeal (including the base of the tongue, tonsils, and pharynx).

5. The incidence of H.P.V-associated oropharyngeal cancer has increased during the past 20 years, especially among men.

6. Biologic factors that may interact with H.P.V infection to increase cancer risk include smoking, decreased immunity, having many children, long-term oral contraceptive use, poor oral hygiene and nutrition, and chronic inflammation.

7. H.P.V may be transmitted by genital contact (oral, touching, or sexual intercourse). The possible modes of transmission in children are controversial; however, it is thought that newborn babies can be exposed to cervical H.P.V infection from the mother.

8. Although the H.P.V vaccine reduces the risk for cervical cancer, women should still get Pap tests and H.P.V screening at regular intervals.

Other Viruses and Microorganisms

1. Human herpes virus type 8 and H.I.V-A.I.D.S are linked to Kaposi sarcoma, and human T-cell lymphotropic virus type 1 is linked to leukemia and lymphoma.

2. Microorganisms involved in carcinogenesis include parasites such as Opisthorchis viverrini (bile duct cancer) and Schistosoma haematobium (bladder cancer).

Chemicals and Occupational Hazards as Carcinogens 1. Synthetic chemicals are widely used in the United States, of which only a fraction have been tested for their health.

2. Exposure to chemicals occurs from air, soil, food, water, personal care products, toys, household products, medications, workplaces, and homes

3. A large number of chemicals are known carcinogens in experimental animals, and it is suspected that most of these are potentially carcinogenic in humans. When adequately tested, all agents known to cause cancer in humans also produce it in experimental animals when adequately evaluated.

4. Chemical carcinogenesis involves genotoxic mechanisms (create genetic damage) and nongenotoxic mechanisms (alter signal transduction).

5. A substantial percentage of cancers of the upper respiratory passages, lung, bladder, and peritoneum are attributed to occupational factors. Notable occupational hazards include dyes, rubber, paint, aromatic amines, benzol, heavy metals, silica, polycyclic aromatic hydrocarbons, sulfuric acid, and chloromethyl ether. Asbestos is linked to an epidemic of mesothelioma and asbestos usage has been banned in most developed countries.

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Incidence and Types of Childhood Cancers

1. Cancer in children and adolescents is rare, but it is still the leading cause of death from disease in this population.

2. Leukemia is the most common type of cancer among children less than 14 years of age. Tumors involving the brain or central nervous system are the second most common type of childhood cancer.

3. The most common cancers among adolescents (15 to 19 years of age) are Hodgkin and non-Hodgkin lymphoma, leukemia, germ cell tumors (particularly testicular), C.N.S tumors, thyroid cancer, and sarcomas.

Etiology

1. The interaction of many factors most likely produces cancer in children and adolescents, a concept referred to as multiple causation or multifactorial etiology.

2. Mutations in proto-oncogenes, tumor-suppressor genes, and mismatch repair genes have been associated with childhood and adolescent malignancies.

3. Risk factors associated with the development of childhood cancer include inherited and acquired genetic and genomic changes, nutrition and diet, immune function, occupational exposure, hormonal variations, and viral illnesses, as well as other individual characteristics, such as biologic, social, or physical environments.

4. Children with Down syndrome have an increased risk for the development of leukemia.

5. Childhood exposure to ionizing radiation, drugs, or viruses has been associated with the risk of developing cancer.

Prognosis

1. Nearly 85% of children and adolescents diagnosed with cancer are cured.

2. Childhood cancer survivors have a greater risk of developing a second cancer during their lifetime compared with the general population.

3. Reasons for improved survival among children and adolescents with cancer include research aimed at identifying less toxic treatments with fewer long-term side effects.

4. Young children are particularly prone to long-term sequelae of cancer therapy. The development of more effective, targeted therapies with fewer side effects is imperative.

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