Molecular Pathogenesis of Cancer PDF

MOLECULAR PATHOGENESIS OF CANCER Cancer cells differ from their normal counterparts in that they have abnormal regulation. Cells lose their normal characteristics and acquire abnormal characteristics that affect the appearance of the cells, the expression of proteins on the cell surface, c...

MOLECULAR PATHOGENESIS OF CANCER Cancer cells differ from their normal counterparts in that they have abnormal regulation. Cells lose their normal characteristics and acquire abnormal characteristics that affect the appearance of the cells, the expression of proteins on the cell surface, cell growth, cell reproduction and cell death. Seven (7) fundamental changes in cell physiology have been proposed that collectively determine malignant cell growth. 1. Self- sufficiency in growth signals. Tumors possess the capability to proliferate without external stimuli, usually resulting from oncogene activation. Proto-oncogenes are normal genes that regulate normal cell growth and repair. Oncogenes are altered proto-oncogenes that promote autonomous cell growth in cancer cells. Oncogenes are like the accelerator of an automobile, resulting in increased cell birth or decreased cell death when expressed. Many cancer cells develop growth self- sufficiency by acquiring the ability to produce the necessary growth factors to which they respond. 2. Insensitivity to growth- inhibitory signals. Tumor suppressor genes, or the brakes of the cell, inhibit cell growth through cell - cycle control and regulation of apoptosis. Alterations in tumor suppressor genes resulting in failure to inhibit tumor cell growth are a key event in many cancers. Tumor suppressor genes are categorized as either gatekeepers or caretakers. Gatekeepers are genes that directly control the growth of tumors by inhibiting cell proliferation and/or promoting cell death. In contrast to gatekeepers, caretaker genes do not directly regulate cell proliferation, but control the rate of mutation. Therefore mutation of a caretaker gene leads to genetic instability that indirectly promotes growth and accelerates conversion of a normal cell to a normal cell. 3. Evasion of Apoptosis. The proliferation of cancer cells may occur not only by the activation of oncogenes or inactivation of tumor suppressor genes, but also by mutations in the genes that regulate apoptosis, or programmed cell death. 4. Defects in DNA repair. The DNA of normal dividing cells is susceptible to damage from environmental agents and to alterations resulting from errors that occur spontaneously during DNA replication. If DNA repair does not occur promptly, malignant transformation of the cell can occur. Individuals born with an inherited mutation of DNA repair genes are at a significantly increased risk of developing cancer. 5. Limitless replication potential. Telomeres are structures at the end of each chromosome that shorten with each cell division. Once the telomeres are shortened with each cell division. Once the telomeres are shortened beyond a certain point, proliferation ceases or apoptosis occurs. In germ cells, telomeres shortening is prevented by the enzyme telomerase, thus enabling these cells to self-replicate extensively. Maintenance of telomere length and telomerase activity is essential for cancer cells to maintain unlimited replication potential and attain immortality. 6. Sustained angiogenesis. Tumors stimulate the formation of a vascular supply, a process called angiogenesis, which is essential for continued tumor growth and metastasis. Tumor cells produce angiogenic factors such as vascular endothelial growth factor (VEGF) to stimulate and sustain blood vessel growth. 7. Ability to invade and metastasize. Metastasis is the spread of cancer cells from a primary tumor to distant sites in the body. It is a complex process requiring tumor cells to break loose from the primary tumor, enter the blood vessels or lymphatic system, and produce a secondary tumor at a distant location. CHARACTERISTICS OF CANCER CELLS 1. ALTERED CELL DIFFERENTIATION In normal cell growth. Cells become more specialized and acquire specific structural and functional characteristics as they mature, a process called Prepared by: [email protected] 1 differentiation. During transformation from a normal cell to a malignant cell, altered differentiation can result from changes in the appearance and metabolism of the cell, the presence of tumor-specific antigens, and the loss of normal function. a. Appearance Changes. Cancer cells vary in size and shape, a feature called pleomorphism. Some are unusually large, whereas others are extremely small. Nuclei may be disproportionately large, or there may be multiple nuclei. A variety of abnormal mitotic features may be present. There maybe an abnormal number of chromosomes, called aneuploidy, or abnormal arrangements of chromosomes. In cancer, differentiation refers to the extent to which cancer cells resemble similar normal cells. Cancer cells vary in their ability to retain the morphologic and functional traits of the original tissue. Cells that are mature in appearance and closely resemble the normal cell are well - differentiated. Cells that grow rapidly and do not have the original tissue’s morphologic characteristics and specialized cell functions are termed undifferentiated. Anaplastic or undifferentiated cell appear cytologically disorganized and have no resemblance to the tissue of origin. The more undifferentiated a malignant cell, the more aggressive it is believed to be. b. Altered Metabolism. Cell membrane changes may result in the production of surface enzymes that aid invasion and metastasis. In addition, a loss of glycoproteins that normally assist in cellular adhesion and organization results in a loss of cell - to - cell adhesion and increases cell mobility. Higher rates of anaerobic glycolysis in the cancer cell also make the cell less dependent on oxygen. Production of abnormal growth factor receptors may independently signal the cell to grow and may increase sensitivity to normal growth factors. Cancer cells may inappropriately secrete hormones or hormone- like substances in an or tissue that does not normally produce or release those hormones, resulting in paraneoplastic syndromes or signs and symptoms not directly related to the local effects of the tumor. For example, in small cell carcinoma of the lung, antidiuritic hormone (ADH) is produced, resulting in hyponatremia. c. Tumor-Specific Antigens. Some tumors produce an excess of specific antigens or produce new tumor - associated antigens marking the cancer cell as “non-self”. An example is the prostate - specific antigen (PSA) which is a protein produced by prostate gland cells. An elevation in PSA may indicate prostate cancer. Certain tumor antigens may be useful as tumor markers and can be used as a diagnostic tool or in monitoring the effectiveness of cancer treatment. d. Altered Cellular Function. The need for cell renewal or replacement is the usual stimulus for cell proliferation. Cell production stops when the stimulus is gone, producing a balance between cell production and cell loss. The rate of normal cellular proliferation differs in each tissue. In some tissues such as bone marrow, hair follicles, or epithelial liming of the GIT, the rate of cellular proliferation is rapid. In other tissues, such as the myocardium, neurons, and cartilage, cellular proliferation does not occur in cancer, proliferation continues once the stimulus initiates the process, and cancer cells progress is continued, uncontrolled growth. Normal control mechanism fail to stop this proliferation. Prepared by: [email protected] 2  Cancer cells also demonstrate a lost of contact inhibition. Normal cells cease movement when they come in contact with another cell and symmetrically arranged themselves around each other. Cancer cells invade others without respect to these constraints. In addition, when normal cells are surrounded by other cells, they simply stop dividing. Cancer cells lack or exhibit decreased contact inhibition of growth, continuing to divide and even piling atop one another. Cancer cells are less genetically stable than normal cells because of the development of abnormal chromosomes arrangements. Chromosomal instability results a new, increasingly malignant mutants as cancer cells proliferate. These mutant cells can can create a surviving subpopulation of advanced neoplasms with unique biologic and cytogenetic characteristics that are highly resistant to therapy. Cancer cells also possess the capacity to metastasize, the HALLMARK of malignant neoplasm. METASTASIS , the spread of cancer cells from a primary site to distant secondary sites, is aided by the production of enzymes on the surface of the cancer cell. 2. TUMOR GROWTH The rate of tissue growth in normal and cancerous tissue depends on three factors: the duration of the cell cycle, the number of cells that are actively dividing, and cell loss. A. Cell cycle - Gap 1, synthesis, Gap 2 and Mitosis B. Cell cycle time Cell-cycle time is the amount of time required for a cell to move from one mitosis to another mitosis, or sum of M, G1, S, and G2. The length of the total cell cycle varies with the specific type of cell. A common misconception is that the rate of cancer cell proliferation is faster than that of a normal cell. Usually cancer cells proliferate at the same rate as the normal cells of the tissue of origin. The difference is that the proliferation of cancer cells is continuous. The length of the Gȏ (Gap zero) phase is the major factor in determining the cell - cycle time. C. Doubling Time In the simplest model for cell growth, a cell divides to produce two daughter cells, each of which then divides, producing four cells, eight cells, and so on. Thus, cell numbers increase in power of two, called exponential growth. The growth rate of tumors is expressed in doubling time. Doubling time is the length of time it takes for a tumor to double its volume. Tumor cells undergo a series of doublings as the tumor increases in size. The average doubling time for most primary solid tumors is approximately 2 months. Rapidly growing tumors such as testicular cancer may double every month, whereas slow - growing tumor such as prostate cancer may double every year. It may take 10 years for tumor to reach 1 cm in size. If only another year, same tumor may grow to 8 cm. Factors that affect doubling time are cell-cycle time, growth fraction, and cell loss by either cell death, differentiation or metastasis. A tumor is usually clinically undetectable until it has doubled 30 times and contains more than 1 billion cells. At this point, it is approximately 1 cm in size and equals 1 gm in weight. With only 10 more doublings, the tumor contains more than 1 trillion cells or weighs 1 kg, which is enough to cause death. Prepared by: [email protected] 3  D. Growth Fraction Because not all tumor divide simultaneously, growth fraction is an important concept in the determination of doubling time. Growth fraction is the ratio of the total number of cells to the number of dividing cells. Tumors with larger growth fractions increase their tumor volume more quickly. As tumor volume increases, growth fraction decreases as a result of hypoxia, decreased nutrient availability, and toxins. In the later stages of tumor growth, only a small portion of cells are actively dividing. Cell growth usually continues only at the periphery of the tumor, with the center becoming increasingly dormant and eventually becoming necrotic. The tumor eventually reaches a point where cell death approximates cell birth, and a plateau is reached. The rapid proliferation of tumor cells followed by the continuous, but slower growth is called the Gompertzian growth curve. The growth curve illustrates the initial exponential growth of cancer cells, followed by the steady and progressive decrease in the fraction of proliferating cells and an increase in the rate of cell death. ROUTES OF TUMOR SPREAD Tumor spread throughout the body can occur by direct extension or local invasion of adjacent organs, metastases by implantation or serosal seeding, and metastases to distant organs by the lymph or circulatory system. Factors affecting tumor spread include the of cell growth, the degree of differentiation, and the location. Local invasion is the first step in the metastatic process and may occur as a function of direct tumor extension. Mechanisms important in local invasion include tumor growth, mechanical pressure, tumor-secreted enzymes, decreased cellular adhesion, and increased motility. Serosal seeding occurs when tumors, which have invaded a bod cavity from surrounding tissue, attach to the surface of an organ within the cavity. Most often, the peritoneal cavity is involved; other spaces such as the pleural cavity, the pericardial cavity, or the joint spaces may be affected. Prepared by: [email protected] 4  The most common route for metastases is via the lymphatic system. Tumor cells entering the lymphatic vessels are carried to regional lymph nodes. Entrapment of the tumor cells may occur in the first lymph node encountered, or the cell may bypass the first node and spread to more distant sites, called skip metastases. For many types of cancer, the first indication of spread is a mass in the regional lymph nodes. For example, an enlarged axillary lymph node may signal breast cancer. A significant feature of a lymphatic system is that the main lymphatic trunk enters the venous system before the veins enter the heart. Therefore the lymphatic and the circulatory systems are interconnected, and cancer cells that enter the lymphatic system are also able to enter the bloodstream. In tumor spread via the circulatory system, the tumor cells usually follow the venous flow that drains the site of the neoplasm. Venous blood from the GIT, pancreas, and spleen is routed through the portal vein of the liver before entering the circulation. Therefore the liver is a common metastatic site for cancers that originate in these organs. Other common sites of metastases in addition to the liver include the lung, bone, and the central nervous system. METASTASIS Metastasis, derived from the Greek prefix meta-, or beyond, is the spread of cancer cells from a primary tumor or organs and distant sites in the body. A cancer cell’s ability to invade adjacent tissues and metastasize to distant sites is its most virulent property and is a distinguishing characteristic of cancer Approximately 60% of patients with invasive cancer have overt or occult metastases at diagnosis. The process of metastasis is a cascade of linked sequential steps. All of these steps must be completed for a metastatic lesion to develop. ( refer to: “ The metastatic cascade image:) A. Growth and progression of the primary tumor. The first requirement for metastasis is rapid growth of the primary tumor. Most tumors must reach 1 billion cells or cm in size before metastasis is possible. B. Angiogenesis at the primary site. Extensive vascularization, or angiogenesis, is necessary for the tumor to exceed 1mm in diameter. The release of angiogenic factors by tumor cells is necessary to stimulate new capillary formation. The growth of the tumor and the rate of spread are correlated with tumor vascularity. C. Local invasion. To reach blood vessels or the lymphatic system, tumor cells must break down the tissue stroma and basement membrane. Several factors are involved in tumor cell invasion. First, rapid tumor growth creates a mechanical pressure that forces finger-like projections of cancer cells into adjacent tissue. Second, increased cell motility can contribute to tumor cell invasion. The lack of adhesion among tumor cells increases the ability of the cancer cells to escape and invade. Third, tumor cells secrete enzymes such a the matrix metalloproteinases that are capable of destroying the basement membrane. Prepared by: [email protected] 5 D. Detachment and embolization. Millions of cells are shed into the circulation daily from locally invasive cancer, but fewer than 0.01% successfully survive to grow into a metastatic lesion. Once in the circulation, tumor cells are vulnerable to destruction by the host immune cells. For protection, tumor cells aggregate with blood cells, primarily platelets, and form fibrin - platelet emboli. This protects the tumor cells and promotes metastasis by enhancing their ability to adhere to the capillary walls of the target organ. E. Arrest in distant organ capillary beds. In many types of cancers, the most frequent location of metastases is the first capillary bed or lymphatic tissue in an organ adjacent to the tumor site. This explains why lung and liver metastases are the first parenchymal metastases seen from most cancers. Others show preference for specific organs, known as organ tropism. For example, ocular melanoma frequently metastasizes to the liver, and prostate carcinoma often spreads to the bone. Factors that may influence certain tumors to metastasize to specific sites include patterns of blood flow or tumor - cell expression of specific surface molecules that prefer specific organs; organs may also attract circulating tumor cells through specific receptors or growth factors. These factors may be the outcome of “cross - talk” between cancer cells releasing cytokines that cause the normal cells to produce substances that recognize receptors on the cancer cells. F. Extravasation. After the tumor cells have arrested or firmly attached themselves to the endothelial cells of a vessel, the tumor cells must penetrate or extravasate through the vessel wall to grow into the extravascular tissue. Arrested tumor cells use the same process to gain entrance through the endothelial basement membrane that was used to gain initial access to the vascular system. Once the endothelium is damaged, tumor cells escape through the vessel wall and invade the organ tissue. G. Proliferation. Once tumor cells arrive in the extravascular tissue, a blood supply and nutrients must be acquired for continued growth. The new environment may differ considerably from the original site. In general, more poorly differentiated cancer cells are better able to adapt to foreign tissues and survive. Prepared by: [email protected] 6 The Metastatic Cascade: ( From KumarV, FaustoN, Abbas A, editors: Robbins & Cotran pathologic basis of disease, ed7, Philadelphia, 2005, Sauders) References:  Langhorne, M., Fulton, J., Otto, S., (2011). Oncology Nursing, 5th Edition, Elsevier (Singapore) PTE LTD  Smeltzer, S., Bare, B., Hinkle, J. & Cheever, K. (2014). Brunner & Suddarth’s Textbook of Medical Surgical Nursing 13th edition Prepared by: [email protected] 7 Prepared by: [email protected] 8