Chapter 11: Cancer Biology

Question 1

Cancer Terminology and Characteristics

Answer 1

1. Cancer is a disease in which abnormal cells divide uncontrollably
   and invade other tissues. A tumor is a new growth, or neoplasm.
2. 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.
3. 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.
4. 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.
5. Carcinoma in situ (CIS) refers to noninvasive epithelial tumors of
   glandular or squamous cell origin. These early–stage cancers are
   localized to the epithelium and have not penetrated the local basement membrane.

Question 2

The Biology of Cancer Cells

Answer 2

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 DNA mutations that alter
   genes, chromosomes, and non–coding RNAs, as well as epigenetic
   changes because of altered chemical modifications of DNA 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.
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. 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 pro inflammatory
   mediators by the cancer cells and adjacent nonmalignant cells.
7. 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.
8. Cancer heterogeneity or diversity arises from ongoing proliferation
   and mutation.
9. Hallmarks of cancer that are primarily genomic alterations include
   sustained proliferative signaling, evading growth suppression,
   genomic instability, and replicative immortality. Other hallmarks
   secondary to genomic change include induction of angiogenesis,
   reprogramming energy metabolism, resistance to destruction, and
   activating invasion and metastasis.
10. 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.
11. Some oncogenes, such as RAS, result from point mutations. Other
    oncogenes can result from genetic translocations. 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 (CML).
12. Tumor-suppressor genes normally regulate cell cycle, but they must
    be inactivated in cancer cells by mutations to each allele, one from
    each parent.
13. A common mutation in cancer cells is inactivation of the tumor suppressor gene tumor protein p53 (TP53), which activates caretaker
    genes, ones responsible for maintaining genomic integrity. Caretaker
    genes control expression of many genes that repair DNA damage,
    suppress cellular proliferation during genomic repair, and initiate
    apoptosis. Inactivation of p53 results in increased mutation rates
    and cancer.
14. In rare families, a germ cell mutation (an inheritable mutation on
    a sperm or egg cell) in a tumor-suppressor gene, such as TP53 or
    the retinoblastoma gene (RB), may lead to a greatly increased risk
    for developing particular cancers.
15. Genomic instability refers to an increased tendency of alterations/
    mutations in the genome during the life cycle of cells. Genomic
    instability may result from increased epigenetic silencing or modulation of gene function.
16. Changes in gene regulation can affect entire networks of signaling,
    not just single genes. Gene expression networks can be regulated
    by changes in microRNAs (miRNAs or miRs) and other non–coding
    RNAs (ncRNAs).
17. Cancer cells are immortal. When they reach a critical age, cancer cells
    activate telomerase to restore and maintain their telomeres, thereby
    allowing cancer cells to divide repeatedly or become immortal.
18. Like many normal adult tissues, cancers can contain rare stem cells
    that provide a source of immortal cells. To fully eradicate a cancer,
    it may be necessary to target the cancer stem cell.
19. 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).
20. 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.
21. Cancer cells are able to reprogram energy metabolism. The successful cancer cell divides rapidly, with the consequent requirement
    for the building blocks of new cells, such as ATP. 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.
22. 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 (4) corrupt the surrounding microenvironment to assist
    tumor growth and dissemination.
23. In cancer, defects in the intrinsic or extrinsic cell death pathways,
    or both, provide resistance to apoptotic cell death.
24. 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.
25. The inflammatory response may contribute to the onset of cancer
    and be manipulated throughout the process to benefit tumor progression and spread.
26. One of the key cells that promote tumor survival is the tumorassociated macrophage (TAM). Most tumors have large numbers
    of TAMs, whose presence may correlate with a worse prognosis.
    Cancer-associated fibroblasts contribute greatly to cancer progression, local spread, and metastasis.
27. Unique antigens and other markers on tumor cells can be recognized by T cells and NK cells of the immune system, leading to
    destruction of the tumor cell.
28. The immune surveillance hypothesis predicts that most developing malignancies are suppressed by an efficient immune response
    against tumor-associated antigens. Therefore the rationale for
    immunotherapy predicts that the immune system could be used
    to target tumor-associated antigens and destroy tumors clinically.
29. 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 (HPV) and hepatitis B virus (HBV), protect against
    initial infection and development of cervical and liver tumors,
    respectively.
30. Cancer cells can evade rejection by the immune system by production
    of immunosuppressive factors, induction of immunosuppressive
    T-regulator cells, evolution of tumor-antigen negative variants, or
    suppressed expression of antigen-presenting MHC class I molecules.
31. Metastasis is the spread of cancer cells from the site of the original
    tumor to distant tissues and organs through the body and is the
    major cause of death from cancer.
32. Metastasis is a complex process that requires cells to have many
    new abilities, including the ability to invade, survive, and proliferate
    in a new environment.
33. Carcinomas undergo a process of epithelial-mesenchymal transition (EMT) during which many epithelial-like characteristics are
    lost (e.g., polarity, adhesion to basement membrane), resulting
    in increased migratory capacity, increased resistance to apoptosis, and a dedifferentiated stem cell–like state that favors growth
    in foreign micro environments and establishment of metastatic
    disease.
34. Invasion, or local spread, consists of loss of cell-to-cell contact,
    degradation of the extracellular matrix (ECM), and increased motility of individual cancer cells. Stromal cells, particularly tumorassociated macrophages (TAMs), are essential to this process.
35. Some cancers appear to selectively home to particular metastatic
    sites, which may be a result of interactions between the cancer cells
    and specific receptors on the small blood vessels in different organs.

Question 3

Clinical Manifestations of Cancer

Answer 3

1. Paraneoplastic syndromes are rare symptom complexes, often caused
   by biologically active substances released from a tumor or by an
   immune response triggered by a tumor, that manifest as symptoms
   not directly caused by the local effects of the cancer.
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 multiorgan energy wasting syndrome where energy
   intake is decreased and energy expenditure is increased. Two factors
   are most significant: muscle loss and inflammation. Cachexia has
   many clinical manifestations including anorexia, early satiety (filling),
   weight loss, anemia, asthenia (marked weakness), taste alterations,
   and altered protein, lipid, and carbohydrate metabolism. Muscle
   wasting involves many protein signaling pathways and inflammatory mediators. 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 the most 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.

Question 4

Diagnosis and Staging of Cancer

Answer 4

1. The diagnosis of cancer requires a biopsy and examination of tumor
   tissue by a pathologist. Cancer classification is established by a
   variety of tests.
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. A
   standard 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. The classification, and hence the treatment decisions, of cancers
   was originally based on gross and light microscopic appearance,
   and is now commonly accompanied by immunohistochemical
   analysis of protein expression. Increasingly, this is supplemented
   by a more extensive molecular analysis of the tumors.
5. Cancer is treated routinely with surgery, radiation therapy, chemotherapy, and combinations of these modalities. However, cancer
   therapy is rapidly evolving, and genetic anaolysis may help determine
   appropriate therapies.
6. Surgical therapy is used for nonmetastatic disease (in which cure
   is possible by removing the tumor) and as a palliative measure to
   alleviate symptoms.
7. Ionizing radiation causes cell damage; therefore the goal of radiation therapy is to damage the tumor without causing excessive
   toxicity or damage to nondiseased structures.
8. 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.
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. Immunotherapy attempts to modify the immune system from a
    cancer-protective state to a destructive condition.
11. Future treatment of tumors will, most likely, use a careful histologic
    and genetic analysis of individual cancers that prescribes a combination of tumor-targeting drugs to simultaneously disrupt multiple
    hallmarks of that particular cancer.