Chapter 14 Flashcards
proto-oncogenes
a large group of genes that produce proteins with the function of promoting cells to enter and complete the cell cycle
Suppressor genes
a set of master control genes that produce proteins with the function of restricting cells from entering the cell cycle and that inhibit movement of a cell from one phase to the next within the cell cycle.
driver mutations
-DNA from suppressor genes and/or oncogenes is changed
-clear linkage to cancer development and growth advantage, or passenger mutations, which are seen within the cancer genome but are not linked to growth advantage.
Neoplasia
-any new or continued cell growth that is nor needed for normal development or for the replace- ment of dead and damaged tissues. It can be benign or malignant.
Benign tumors
- a type of neoplasia that does not share most of the characteristics of cancer cells. Although benign tumors are abnormal, they arise from normal cells and retain most normal cell characteristics.
-Their growth is not invasive; however, depending on location, they can cause death.
-Some examples of benign tumors include uterine fibroids (leiomyomas), fat tumors (lipomas), colon polyps (intestinal epithelial adenomas), nerve fibers (neurofibromas), and skin moles (nevi).
Characteristics of Benign Tumor Cells
Appearance
-Benign tumors arise from normal cells and retain a normal differentiated (specialized) appearance.
-Their specific morphology is the same as that of the parent cells, even if their location is not.
-They also retain a small nuclear-to-cytoplasmic ratio.
Function
-Benign tumors usually retain the differentiated function or specialized functions of the parent cell.
-For example, not only do the cells of intestinal adenomas look like normal intestinal cells, but they also produce the same substances.
Adherence
-Benign tumors may grow in the wrong place within the body, such as the growth of endometrial tissue on an ovary and not in the uterus, but they do produce most cell adhesion molecules.
-As a result, these cells adhere tightly to one another and do not migrate.
Ploidy
-With few exceptions, tumor cells that are totally benign are diploid and do not display abnormal chromosome numbers or structures.
-Exceptions include benign meningiomas, which are ofren missing the chromosome number 22, and lipomas, which often have structural rearrangements of chromosomes 6, 12, or 13.
Cell Growth
Benign tumors have continuous or inappropriate cell growth unnecessary for normal function. They serve no useful purpose.
-Benign tumor cells can grow by hyperplasia or hypertrophy but do not have the ability to invade other tissues or organs.
-Their growth occurs by simple, nonessential expansion.
-Although growth may continue beyond an appropriate time, the rate of growth is slower than normal.
Pathologic Potential
-The mere existence of benign tumor cells indicates that the strict regulation of growth has been overcome to some degree.
-In many benign tumors, growth is slow and may even stop eventually. -Other benign tumors, however, carry a risk that growth regulation will continue co deteriorate and a malignant tumor (cancer) however, carry a risk that growth regulation will continue co deteriorate and a malignant tumor (cancer) will result. -For example, intestinal adenomas have a high potential to become malignant, although considerable time passes (up to 10 years of growth) before this happens. (This is why everyone over 50 years of age should have a regularly scheduled colonoscopy every 10 years so that polyps can be removed and colon cancer prevented.)
-Benign tumor cells become cancerous as the result of inhibited suppressor gene function and/or enhancement of oncogene function.
Cancer
-disease of cells
-arise from normal cells
- Humans are constantly exposed to personal and environmental conditions that can mutate the DNA, change the genes, and alter the normal regulation of cell growth.
-Such changes can transform a normal cell into a cancer cell.
-This type of transformation that causes cancer development is termed carcinogenesis, oncogenesis, or malignant transformation.
Carcinogens
-Substances capable of causing genetic mutations that lead to cancer development
- The changes cause cells to always be abnormal, have no useful purpose, and invade normal body tissues and organs.
Characteristics of Cancer Cells
Appearance
-Cancer represents a continuum of progression from just barely malignant, in which a normal cell has been transformed into a cancer cell but still has structural components that cause it to remain at the site in the tissue in which it originally developed (in situ), to a highly malignant and aggressive cell with metastatic tendencies.
-Thus, there are degrees of malignancy.
-Over time, cancer cells eventually lose all the specific differentiated appearance of the cells from which they arose and become anaplastic as small, round cells with a larger nuclear-to-cytoplasmic ratio.
-Early in the cancer continuum, cancer cells may still show some normal cell appearance features, but these are later lost until no parental cell features are retained.
-A diagnosed cancer that has lost all features of the parent cell is designated as a tumor of unknown origin.
Function
-In the evolution of cancer from nearly normal to highly malignant, cancer cells gradually lose most or all differentiated functions that the parent cells performed.
-They become less differentiated in both appearance and specialized function.
Adherence
-The ability to produce cell adhesion molecules (CAMs) is usually lost in cancer cells.
-They adhere poorly to each other and can easily break off from a formed tumor.
-This loss of adherence allows cancer cells to migrate into surrounding tissues and enter blood vessels in order to travel to distant sites.
-The invasion of nearby and distant tissues is unique to cancer cells and is a common cause of death.
-For example, if breast cancer remained only within the breast, a nonviral organ, it would not kill the patient.
-However, breast cancer cells do travel, invade vital organs (e.g., brain, bone marrow, lungs, liver), and disrupt their functions enough to cause death.
Ploidy
-Early in the cancer process, the cancer cell’s chromosomes may continue to be normally diploid.
-As they become more malignant, they usually become aneuploid, with gains or losses of whole chromosomes, chromosome breakage, and the structural rearrangemenrs of chromosomes.
-Often, the more malignant a cancer cell becomes, the greater the degree of aneuploidy it has.
-Some chromosomal rearrangements are unique to a cancer type and can be used to identify it as a specific cancer type.
-These unique types of aneuploidy may indicate which oncogenes are overexpressed in a tumor and may be able to be controlled through targeted therapy.
-For example, a chromosome rearrangement in which the ends of the q arms of chromosome 22 are translocated to the q arms of chromosome 9 is close to a promoter site and results in the activation of a special tyrosine kinase (TK) that converts normal bone marrow cells into a more rapidly growing disorder called chronic myelogenous leukemia.
-This special TK is inhibited by the targeted therapy drug imatinib mesylate (Gleevec).
-This drug works only on cancer cells that overexpress this special TK.
Cell Growth
-Cancer cells no longer respond to external or internal signals.
-They are not contact inhibited and continue to divide even when too many cells are already present and nutrition stores are low.
-This loss of contact inhibition allows the persistence of cancer cell division regardless of how many cancer cells are occupying a given space.
-Without treatment, they persist in continued cell division until the host dies.
-Cancer cells also do not respond to signals for apoptosis.
-They do not experience a reduction of telometric DNA with cell division, even though they may not have particularly long telomeres.
-Cancer cells have large amounts of telomerase, which maintains their telomeric DNA.
-Suppressor gene regulation of cell division appears lost or defective in cancer cells, and oncogenes are then overexpressed, which leads to uncontrolled mitosis.
-They do not go through the cell cycle more rapidly than do normal cells; they just reenter the cell cycle quickly, spending very little time in the reproductive resting state of G0, during which the cell provides its specialized function.
-The three known cell cycle checkpoints are not effective, allowing damaged DNA to be unrepaired as it moves through the cell division process with promitotic forces being unopposed.
-Usually, one or more suppressor genes are disabled and cannot restrict oncogene expression.
-With excessive oncogene expression, cyclins and cyclin-dependent kinases (CDKs) are overproduced, and cell division occurs inappropriately and continually. (Using the car example described in Chapter 3, the car driver and/or the car’s brakes are nonfunctional, so acceleration goes wild.)
-Because highly malignant cancer cells divide almost continually, their mitotic index (the percentage of cells within a block of tissue that are actually in the cell cycle at any point in time) is relatively high, usually greater than 50%.
Immortality
-Cancer cells are considered immortal because they do not respond to apoptotic signals and are resistant to natural cell death.
-Unlike normal cells, they do not have a preprogrammed number of cell divisions.
-One feature of cancer cells is that additional gene changes continue to occur that alter the plasma membrane to enhance uptake of all needed nutrients even though they can tolerate very low levels of nutrients.
-When limited nutrients are present in the environment, cancer cells can take them in more efficiently than the surrounding normal cells, leaving normal cells in a starved and weakened condition.
-One example is the increased cancer growth due to the use of the nutrient glutamine by the myc oncogene.
Malignant Transformation
Aka
Carcinogenesis
Aka
oncogenesis.
The steps of the process are initiation, promotion, progression, and metastasis
[Malignant Transformation]
Initiation
-The initial step in malignant transformation is mutating the DNA in such a way that either suppressor genes cannot perform their cell growth regulation functions or oncogenes become resistant to suppressor gene control.
-Any substance or event that can damage DNA has the potential to mutate suppressor genes or oncogenes and is a carcinogen.
-irreversible event that can lead to cancer development if the cell’s mitotic ability remains intact.
-If a cancer cell cannot divide, it cannot progress to widespread malignant disease.
-However, when conditions favor the continuing growth of even one transformed cell, widespread malignant disease can occur.
-This is known as the monoclonal (“from one cell”) origin of cancer.
-Initiation is a required step in carcinogenesis.
-Without initiation, even if the remaining steps occur, cancer does not develop.
[Malignant Transformation]
Promotion
-the process of enhancing the growth of initiated cells over time
-the process of enhancing the growth of initiated cells over time
-The time between initiation and the development of an identifiable tumor is the latency period, which ranges from months to years.
- The length of the latency period varies depending on the following: the strength of the carcinogen (more powerful carcinogens result in a shorter latency period), whether the tissue is also exposed to additional carcinogens (cocarcinogens), the amount of exposure to promoters (greater exposures result in a shortened latency period), and the individual’s resistance to cancer development
-Promoters are substances or conditions that enhance (promote) the growth of the initiated cancer cell. Pro- motion can also shorten the latency period. Promoters include naturally occurring hormones, such as estrogen, testosterone, and insulin; drugs; and a wide variety of chemicals. For example, when cervical epithelial cells have been initiated by viral infection or exposure to cigarette smoke or another chemical, growth is enhanced by the presence of the woman’s own naturally secrered estrogen or progesterone. -Thus, the normal hormone is serving as a promoter.
-Some carcinogens have both initiating ability and promoting ability. These are known as complete carcino- gens because additional exposure to another promoter is not needed for cancer to develop. A few examples of complete carcinogens include radiation, benzopyrene, naphthylamine, and nitroquinolone.
[Malignant Transformation]
Progression
-After sufficient cancer cells have been promoted enough that an identifiable tumor exists, other conditions are needed for this tumor to become as malignant as possible.
-Progression is the continuing genetic changes that occur in cancer cells that alter thier physical, biochemical, and metabolic processes, and confer survival advantages to these cells.
-The most important changes allow cancer cells and tumors to develop a separate blood supply and enhance cellular nutrition.
-In small tumors, nutrition occurs by diffusion, which is not efficient after a tumor is larger than 1 cm.
-With increased growth, tumor cells become hypoxic and begin to secrete angiogenesis factors like vascular endothelial growth factor (VEGF), which normal tissues may secrete under hypoxic conditions.
-VEGF stimulates nearby blood vessels and capillaries to branch into the tumor, establishing a tumor blood supply and improving the availability of tumor nutrition.
-Other changes brought about by progression include membrane permeability changes.
-Many normal cells require insulin and insulin receptors to allow glucose to enter the membrane.
-Cancer cell membranes become directly permeable to glucose so that insulin and insulin receptors are not needed.
-However, glucose uptake is increased further in the presence of insulin.
-Cancer cell membranes become even more efficient at amino acid uptake. As a result of these changes, cancer cells are able to meet their increased metabolic needs quickly and often at the expense of normal cells.
-Thus, through progression, cancer cells and tumors acquire selection advantages that allow them to live and divide no matter how the conditions around them change. Over time, cancer cells become more and more malignant, expressing fewer and fewer normal cell features.
-primary tumor
-the original tumor, usually identified by the tissue from which and in which it first arose (e.g., ovarian cancer, colorecral cancer, prostate cancer).
-When primary tumors are located in vital organs, such as the brain or lungs, their excessive growth interferes with the performance of vital functions and leads to death.
-When primary tumors are located in soft tissue, tumor expansion can occur with little or no damage to surrounding tissue.
-However, most malignant tumors do nor remain in the tissues in which they arise.
[Malignant Transformation]
Metastasis
-the spread of cancer cells from the primary tumor to other body areas, where they grow and damage additional tissues and organs, often leading to death.
- One of the advantages acquired by cancer cells during progression that allows metastasis to occur is the loss of cell adhesion molecules (CAMs), making cancer cells lose their contact inhibition so that they are poorly adherent to each other.
-An additional advantage is the expression of enzymes on the cancer cell’s surface that makes these cells able to penetrate other tissues and blood vessel walls.
-Cancer cells then form secondary tumors (metastatic tumors) by breaking off from the primary tumor.
-Secondary tumors can form by extension into nearby tissues via (I) the bloodstream, (2) the lymphatic system by lymph nodes, and/or (3) across the thoracic, peritoneal or abdominal body cavity (transcoeliomic) to establish colonies in remote tissues.
-Even though the tumor is now in another organ, it is still a cancer from the original parent tissue. For example, when prostate cancer spreads to the bone and lymph nodes, it is prostate cancer in the bone and lymph nodes, not bone cancer and not lymphoma.
-Metastasis is a complex process that requires many steps over time. Most steps result from continued genetic changes through progression.
-Many cancers have a predictable pattern of metastasis. Table 14-2 lists the secondary tumor sites for metastasis of common tumors.
-Although other mechanisms for metastasis to distant sites exist. cancers spread locally by spreading into the neighboring tissue.
-Regional spread occurs through the blood stream travel to tissues or organs that are close to the primary site. When malignant cells travel to distant sites. the process is called metastasis.
-Metastatic sites are often in distant organs with extensive capillary networks such as the lung and liver.
-The most common way cancers metastasize is via the lymph nodes and circulation. depending on the tumor type.
Sporadic cancer
-cancer that usually occurs as a result of environmental exposure or unknown factors and does not have any observable pattern of inheritance within a kindred.
- At the cell level, mutations through carcinogenesis have occurred, disrupting the normal regulation of cell division, usually among somatic cells.
-These cancers are not present in higher-than-expected levels within three or more family generations.
