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Week 11, Cancer

Terms in this set (29)

-Different lesions will have different causes, different rates and patterns of progression, and different responses to treatment. Cancer classification starts with knowing the site of origin and microscopic appearance of the lesion, but can extend to a detailed description of critical genetic changes in the cancer.
- Benign tumors, which are not referred to as cancers, are usually encapsulated and well differentiated. They retain some normal tissue structure and do not invade the capsules surrounding them or spread to regional lymph nodes or distant locations. Benign tumors are generally named according to the tissue from which they arise, and include the suffix "-oma." For ex. A benign tumor of the smooth muscle of the uterus is a leiomyoma, and a benign tumor of fat cells is a lipoma.
-Some tumors initially described as benign can progress to cancer and then are referred to as a malignant tumor. These tumors are distinguished from benign tumors by their more rapid growth rates and specific microscopic alterations, including loss of differentiation and absence of normal tissue organization. One of the hallmarks of cancer cells, as seen under the microscope is anaplasia, the loss of cellular differentiation irregularities of the size and shape of the nucleus, and the loss of normal tissue structure. Malignant tumors may present with different of encapsulation; some lack a capsule, and even if a capsule is apparent, its integrity has been compromised so that tumor cells can grow to invade nearby blood vessels, lymphatics, and surrounding structures. 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.
Alternations in Progrowth and Antigrowth Signals
Cancer cells must have mutations that enable them to proliferate in the absence of external growth signals. To achieve this, some cancer acquire the ability to secrete growth factors that stimulate their own growth, a process known as autocrine stimulation. Other cancers have an increase in growth factor receptors.
-Alternatively, the signal cascade from the cell surface receptor to the nucleus may be mutated in the "on" position. Up to one third of all cancers have an activating mutation in the gene for an intracellular signaling protein called RAS. This mutant RAS stimulates cell growth even when growth factors are missing. Cells also usually receive diverse "antigrowth" signals from their normal milieu. Contact with other cells, with basement membranes, and with soluble factors all normally signal cells to stop proliferating. These mechanisms can put a halt to unregulated cell growth. In addition, this normal antigrowth signal must be inactivated or ignored. Common mutations that subvert the antigrowth signal include inactivation of the tumor-suppressor retinoblastoma or conversely, activation of the protein kinases that drive the cell cycle, the cyclin-dependent kinases. Next, cells have a mechanism that causes them to self-destruct when growth is excessive and cell cycle checkpoints have been ignored. This self-destruct mechanism called apoptosis is triggered by diverse stimuli, including normal development and excessive growth. The pathway to apoptosis is disabled in advanced cancers. The most common mutations conferring resistance to apoptosis occur in the TP53 gene.
Cancer invasion and metastasis
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 characteristics of cancer, and is the major cause of death from cancer.
-Invasion, or local spread, is a prerequisite for metastasis and is the first step in the metastatic process. In its earliest stages local invasion may occur by direct tumor extension. Eventually, however, cells migrate away from the primary tumor and invade the surrounding tissues. Mechanisms important in local invasion may occur by direct tumor extension. Eventually however, cells migrate away from the primary tumor and invade the surrounding tissues. Mechanisms important in local invasion include recruitment of macrophages and other cell types to the primary tumor,, where they promote digestion of connective tissue capsules and other structural barriers by secreted proteases; changes in cell to cell adhesion, often by changes in the expression of cell adhesion molecules such as cadherin's and integrin's, making the cancer cells more slippery and mobile; and increased motility of individual tumor cells.
- Tumors that are encased in a capsule, such as breast ductal carcinoma, must be breakdown the capsule in order to initiate local spread.
-To transition from local to distant metastasis, the cancer cells must also be able to invade to local blood and lymphatic vessels, a task facilitated by stimulation of neoangiogenesis and lymphangiogenesis by factors such as VEGF. Finally, a successful metastatic cell must be able to survive in the circulation, attach in an appropriate new microenvironment, and multiply to produce an entire new tumor, similar, to the characteristics of a cancer stem cell.
-Cancers often spread first to regional lymph nodes through the lymphatics and then to distant organs through the bloodstream. A cancer's ability to establish a metastatic lesion in a new location requires that the cancer both attach to specific receptors and survive in the specific environment.
Pain- There is little or no pain during the early stages of malignant disease. Significant pain can occur in many individuals who are terminally ill with cancer. Direct pressure, obstruction, invasion of a sensitive structure, stretching of visceral surfaces, tissue destruction, infection, and inflammation all can cause pain.
Fatigue- the most frequent reported symptom of cancer treatment. The exact mechanisms that produce fatigue are poorly understood. Suggested causes include sleep disturbances, various biochemical changes secondary to disease and treatment, numerous psychosocial factors, level of activity, nutritional status, and other environmental and physical factors.
Anemia-commonly associated with malignancy, with 20% of persons diagnosed with cancer having hemoglobin concentrations less than 9g/dl (normal value = 15g/dl). Mechanisms of anemia include chronic bleeding (resulting in iron deficiency), severe malnutrition, cytotoxic chemotherapy, and malignancy in blood-forming organs. Chronic bleeding and iron deficiency can accompany colorectal or genitourinary malignancy. Iron also is malabsorbed in individuals with gastric, pancreatic, or upper intestinal cancer.
Leukopenia and thrombocytopenia- causes can include many chemotherapeutic drugs because they are toxic to the bone marrow, often causing granulocytopenia and thrombocytopenia. Granulocytopenia also can result from radiation therapy if it encompasses significant areas of the bone marrow.
Infection- most significant cause of complications and death in patients with malignant disease. When the absolute granulocyte count falls below 500 cells per uL, the risk of serious microbial (bacterial and fungal) infection increases. Advanced disease can predispose to infection and immunosuppression from the underlying cancer and the radiotherapy and chemotherapy used to treat it. The prevalence of hospital-acquired (nosocomial) infections increases because of indwelling medical devices, inadequate wound care, and the introduction of microorganisms from visitors and other individuals.
The era of modern chemotherapy began with the observation in World War II that mustard gas exposure caused suppression of the bone marrow. Related compounds, such as nitrogen mustard and cyclophosphamide, were then tested and produced clinical responses in hematologic malignancies including lymphomas. Also in the late 1940s, based on the remarkable clinical observation that the vitamin folic acid could increase leukemia growth, anti-folate drugs were developed (leading ultimately to methotrexate) that produced remissions in previously untreatable leukemia's.
-All chemotherapeutic agents take advantage of specific vulnerabilities in target cancer cells.
-Some cancer cells are highly sensitive to DNA-damaging agents, such as cyclophosphamide and anthracyclines, because of the oncogenic mutations that accelerate the cell cycle and DNA synthesis.
-Single chemotherapeutic agents often shrink cancers, but these drugs given alone rarely is ever provide a cure. Hence, chemotherapy drugs are usually given in combinations designed to attack a cancer from many different weaknesses at the same time and to limit the dose and therefore the toxicity of any single agent. Cancers contain a very large number of cells, and commonly a small fraction of those cells may be resistant to a particular drug. However, those cells are likely to be sensitive to the second or third drug in a chemotherapy cocktail.
-Chemotherapy can be used for several distinct purposes. 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. As with induction chemotherapy, the effectiveness, or lack thereof of neoadjunvant therapy can be measured (for ex., which follow up scans). Neoadjuvant therapy can shrink a cancer so that surgery may spare more normal tissue.
Diet: Polycyclic Aromatic hydrocarbons and heterocyclic aromatic amines: Both generated by meat protein (overcooked beef)
Xenobiotics: toxic, mutagenic, carcinogenic chemicals found in the human diet. Also found in diesel fumes, pesticides, water supplies, medications. React with macromolecules (proteins / dna) or cell structures to cause damage.
Defense: Detoxification enzymes (2) antioxidant systems.
Phase I activation enzymes: activate xenobiotics, P450 family / aldehyde oxidase / xanthine oxidase
Phase II detoxification enzymes: Protect against reactive intermediates / nonactived xenobiotics. Located in liver → block carcinogens in GI / portal circulation.
Phenotype Expression Effected by: methylation of promoter genes or histones. DNA can also be hypomethylated → overexpression of transcription or proto-oncogenes, increased recombination and mutation and loss of imprinting → Cancer.
Aberrant DNA methylation: Occurs in colon, lung, prostate, and breast cancers.
Polycyclic Aromatic hydrocarbons and heterocyclic aromatic amines: Both generated by meat protein (overcooked beef)

These ionizations can lead to irreversible damage or indirect damage from formation and attack by water-based free radicals. IR affects many cell processes, including gene expression, disruption of mitochondrial function, cell cycle arrest, and cell death. IR is a potent DNA damaging agent that causes cross-linking, nucleotide base damage, and single- and double-strand breaks. Damage to DNA and disrupted cellular regulation processes can lead to carcinogenesis. The double-strand break (DSB) is considered the characteristic lesion observed for the effects of IR. DSBs are mostly repaired by the nonhomologous end joining (NHEJ) pathway. This pathway is efficient for joining the DNA broken ends; however, errors can occur. Irradiated human cells unable to execute the NHEJ are supersensitive to the introduction of large-scale mutations and chromosomal aberrations.
transgeneration effects: radiation may induce a type of genomic instability in the progeny (descendants) of the directly irradiated cells over many generations of cell irradiation. The instability leads to an increased rate of mutations/ chromosomal aberrations in these distant eprogeny.
"nontargeted" effects the directly irradiated cells can lead to genetic effects in bystander cells or innocent cells, even though these latter cells received no direct radiation exposure.

Although bystander and transgeneration IR effects are associated with induced genomic instability leading to chromosome aberrations, gene mutations, late cell death, and aneuploidy, all of these effects may be epigenetically mediated. The epigenetic changes include DNA methylation, histone modification, and RNA-associated silencing. Bystander effects are considered manifestations of a radiation-induced genomic instability. These effects could lead to a "hypelinearity" response— a higher level of risk per unit dose. Oxidizing mediators increase the expression of proteins involved in gap junction intercellular communication (GJIC). Some data support a role for oxidative stress and GJIC in radiation-induced bystander effects.
Ultraviolet radiation (UVR) can emanate from both natural and artificial sources;--> most people is sunlight. UVR is now known to cause specific gene mutations; for example, squamous cell carcinoma involves mutation in the p53 gene, basal cell carcinoma in the patched gene, and melanoma in the p16 gene. The development of melanoma is associated with the loss of E-cadherin and the appearance of N-cadherin adhesion molecules. UV light induces the release of tumor necrosis factor (TNF) in the epidermis, which may reduce immune surveillance against skin cancer.

Skin exposure to UVR and IR, as well as xenobiotic agents or drugs, → ROS→ overwhelm tissue antioxidants and other oxygen-degrading pathways→ Antioxidants decrease ROS and oxidative stress and other protective mechanisms, including DNA repair and apoptosis. UVR activates free radicals important in regulating genes that induce inflammation; inflammation is critical for tumor progression. A point mutation in the B-raf (BRAF) proto-oncogene increases BRAF kinase, which activates the mitogen-activated protein kinase pathway. Health risks associated with electromagnetic radiation (EMR) are controversial. Exposure to electric and magnetic fields is widespread. EMRs are a type of nonionizing, low-frequency radiation without enough energy to break off electrons from their orbits around atoms and ionize the atoms. Microwaves, radar, and power frequency radiation associated with electricity and radio waves, fluorescent lights, computers, and other electric equipment all create EMRs of varying strength. A meta-analysis found a consistent pattern of an increased risk for acoustic neuroma and glioma in individuals using cell phones for more than 10 years. Increasing evidence has indicated that the mechanism of harm from EMR involves induction of cell stress and damage to intracellular components, free radical formation, and altered protein conformation. Adverse EMR has been reported to affect DNA synthesis and alter cell division, electrical charge of ions, and molecules within cells. 8. Identify behaviors and environment agent exposures associated with carcinogenesis. Study pages 277, 278, and 281; refer to Boxes 10-4 through 10-6.
Environmental Carcinogens: For colon cancer, physical activity increases gut motility, which reduces the length of time (transit time) that the bowel lining is exposed to potential mutagens. For breast cancer, vigorous physical activity may decrease exposure of breast tissue to ovarian hormones, insulin, and insulin-like factor. A randomized trial found that after 12 months of moderate-intensity exercise, postmenopausal women had significantly decreased serum estrogens. Physical activity also helps prevent type 2 diabetes, which has been associated with risk of cancer of the colon and pancreas.

Occupational: asbestos→ mesothelioma and lung cancer. Carcinoma of the bladder→ manufacture of dyes, rubber, paint, and aromatic amines. Benzol inhalation→ leukemia in shoemakers, rubber cement factories, explosives, and dyeing industries. Other notable occupational hazards→ high-nickel alloy, chromium VI compounds, inorganic arsenic, silica, polycyclic aromatic hydrocarbons, sulfuric acid, and chloromethyl ether.

Occupational exposure→ diesel exhaust → lung cancer. Air pollution can be carcinogenic. A concerns include industrial emissions, including arsenicals, benzene, chloroform, formaldehyde, sulfuric acid, mustard gas, vinyl chloride, and acrylonitrile. Indoor pollution generally is considered worse than outdoor pollution, partly because of cigarette smoke. Environmental tobacco smoke (ETS) → reactive oxygen free radicals → DNA damage. Radon is a natural radioactive gas derived from the radioactive decay of uranium that is ubiquitous in rock and soil; it can become trapped in houses and gives rise to radioactive decay products known to be carcinogenic to humans. Most of the lung cancers associated with radon are bronchogenic; however, small cell carcinoma does occur with greater frequency in underground miners. Strong evidence indicates a higher risk of bladder, skin, and lung cancers after consumption of water with high levels of arsenic.