Chapter 3

CancerDefinition:

Cancer is the growth of abnormal cells that tend to invade neighbor tissue and spread to distant body sites ( uncontrolled cellular proliferation that knows no limits and serves no purpose).

There are more than 100 forms of the disease.

For a cell to become cancerous, the following genetic alterations must occur :

- prompt cell growth;- inactivate genes (normally slow growth);- allow cells to keep dividing,- allow cells to live on with abnormalities (stop apoptosis).- recruit normal cells to support and nourish them, and

- prevent the immune system from destroying them.

Physiologic Concepts

A. Cellular Reproduction All cells reproduce during embryogenesis, only certain cells continue to do so after the first few months following an after birth.

Cells that reproduce, such as liver, skin, and GIT cells, split into two new daughter cells.

Cells that do not reproduce after birth (skeletal muscle, nerves) do not go through this.

B. Cellular Differentiation Normal cells differentiate during development (becomes specialized in structure and function). The more highly differentiated a cell,

the less frequently it will go through the cell cycle to reproduce and divide. (Neural cells, which do not

reproduce, are highly differentiated cells).

Cells that seldom or never go through the cell cycle are unlikely to become cancerous, while cells that go through the cell cycle frequently are more likely to become so.

C.The Cell Clock Reproduce occurs in a predictable number of times, then stops. This system is important because if cells divided indefinitely we would have many more cells than is compatible with life.

Pathophysiologic ConceptsUncontrolled Cellular ReproductionCancer cells go through the cycle more often than normal, causing accumulation of abnormal cells (short interphase) .

The cells become independent of normal growth control signals (autonomy), so do not respond to growth inhibitors released by neighboring cells or inhibitory

growth factors and hormones traveling in the circulation.

AnaplasiaAnaplasia refers to regression of a differentiated cell to a less differentiated stage. Cancer cells demonstrate various degrees of anaplasia. By undergoing anaplasia, a cancer cell loses its ability to perform its previous

functions and bears little resemblance to its tissue of origin. Highly anaplastic cells may appear embryonic and begin to express functions of a different cellular type. Some cancer cells may become ectopic sites of hormone production. For instance, antidiuretic hormone (ADH) or adrenocorticotrophic hormone (ACTH).

Tumor Cell MarkersSome cancer cells release tumor cell markers, which are specific substances into the blood, urine, or spinal fluid. Tumor cell markers may be specific antigens present on the cancer cells. Some tumor antigens are similar to fetal antigens and are called oncofetal antigens. Because fetal antigens often do not provoke an immune response, they may mask the

tumor against the host's immune system.Clinical Implications of Tumor Cell MarkersTumor cell markers are clinically important because they offer a means of identifying certain cancers as well as a cancer's progression before, during, and after treatment. For instance, if a specific tumor cell marker is identified in a patient, it suggests that cancer may exist in the

person, and further diagnostic evaluation is necessary. Furthermore, in patients with a known malignancy, if after radiation or chemotherapy the tumor cell marker is not detectable, it suggests that the cancer is in remission. If, however, the tumor cell marker fails to decrease during therapy or reappears in high concentration after therapy, the tumor is unlikely to be in remission.

Examples of Tumor Cell Markers

Alpha-fetoprotein for liver ,ovarian and testicular cancers Carcinoembryonic antigen for colorectal cancer Human chorionic gonadotropin (hCG) for many tumors, including usually cancer of the uterus Acid phosphatase and prostate-specific antigen (PSA) for prostate cancer

CA-125, a protein released from female reproductive organs as well as from the lining of the chest and peritoneal cavities. It increases with inflamed or injured tissue and is a marker for ovarian cancer.

N.B., Failure to detect a tumor cell marker does not mean that an individual is cancer-free.

Tumor Growth RateImportant characteristics that affect a tumor's growth rate include the person's age, sex, and overall health

and nutritional status. The status of the host's immune system is also important. An individual who is immune-suppressed may be unable to recognize a tumor as foreign. Certain hormonal states (e.g., pregnancy) may stimulate certain tumor growth rates, while stress may affect the host's ability to restrict the development or growth of a tumor.Important characteristics of a tumor that affect its growth rate

include its location in the body and its blood supply. The degree of cellular anaplasia and the presence or absence of tumor growth factors are also important. Descriptions of Tumor Growth and SpreadGrowth and spread of a tumor is often described clinically. Tumor treatment often depends on the grade and stage of the cancer.

Grading: An assessment of the tumor based on the degree of anaplasia it demonstrates. For example, poorly differentiated (highly anaplastic) cells are assigned a high grade. Staging: A clinical decision concerning the size of a tumor, the degree of local invasion, and the degree to which it has spread to distant sites in a given individual.

Local Growth of a Tumor

Growing tumors injure and kill neighboring cells both by compressing the cells and blocking off their blood supply. Tumor cells also appear to release chemicals or enzymes that cause the neighboring cells to lyse and die. When neighboring cells die, the tumor can easily grow to occupy that space. To grow beyond a certain size, tumors must stimulate the development of their own

blood supply( angiogenesis) to meet high metabolic demands.

MetastasisMetastasis is the movement of cancer cells from one part of the body to another. Metastasis usually occurs through the spread of cancer cells from the original (primary) site in the blood or lymph to a new, secondary site.

The term malignancy refers to the ability of a tumor to metastasize.

Process of MetastasisSteps involved in the metastasis of a primary tumor to a distant site include :1-DetachmentTo metastasize, cancer cells must first detach from their primary cluster. Normal cells detach with

difficulty and if it has become detached from its neighbors, it undergoes apoptosis. Cancer cells, in contrast, easily lose adhesion with like cells and begin to enter the circulation.2- InvasionTo spread to distant sites, detached tumor cells must gain entrance to a blood or lymph vessel by secreting specific enzymes that attack the integrity of the tissue.3-Dissemination and Seeding

Movement of tumor cells in the blood or lymph is called dissemination. Some tumor cells will get caught in a capillary or lymph network downstream from the primary site. Although many cells may die, a few tumor cells at this new site may survive and begin to seed the area. The more cells that detach from the primary tumor, the more likely it is that at least one will survive the journey

and start a new tumor growth elsewhere.When the secondary site has reached a critical size, the tumor cells will again begin to produce tumor angiogenesis factor and new blood vessel formation will be initiated to support growth of this secondary site.

Progress of a Metastasizing TumorBecause cancer cells tend to be large, most lodge in the nearest

lymph or capillary bed downstream from the primary tumor site. Because of this, the lungs, which receive systemic venous blood directly from most organs, are the most common sites of metastasis. Venous blood from the gastrointestinal (GI) tract and pancreas travels first to the liver which is the most common site of cancers from these organs. N. B., Metastasis is evaluated by observing for secondary sites in

the lymph nodes nearest to the primary site, and then progressively further from this site. Exceptions to this rule are tumor cells that show a striking preference to colonize certain tissues not necessarily downstream. The classic example of this preference is the tendency of prostate cancer to metastasize to bone.The Immune System and Cancer

The presence in the blood of antibodies, T cells, and natural killer (NK) cells produced against specific tumor antigens has been confirmed in individuals with cancer. In addition, individuals who are immunocompromised, including those with AIDS or those taking immunosuppressant drugs, have an increased chance of developing cancer. All of these findings demonstrate clearly that the immune and inflammatory

systems have important roles in fighting and preventing cancer.Categories of Cancer The suffix oma is usually added to the tissue term to identify it as a tumor, either benign or cancerous.Carcinoma is a cancer of the epithelial tissue, including cells of the skin, testis, ovary, mucus-secreting glands, melanin-secreting cells, breast, cervix, colon, rectum, stomach, pancreas, and esophagus.

Lymphoma is a cancer of the lymphatic tissue, including the lymph capillarie, spleen, various lymph nodes, and lymph vessels. Sarcoma is a cancer of the connective tissue, including cells found in the muscle and bone.Glioma is a cancer of the glial (support) cells of the central nervous system.Carcinoma in situ is a term used to describe abnormal epithelial cells that are as yet confined to a certain

area and thus considered preinvasive lesions.

The Theory of CarcinogenesisCancer development is a multi-step process that usually requires decades to occur. The first step in carcinogenesis is thought to be a mutation in the DNA during DNA replication (copying). Although mistakes in DNA copying are not unusual, most mistakes are

identified by proofreading enzymes that travel down the DNA strands to check for errors, signaling the cell cycle to stop for repair when necessary. If a mistake cannot be repaired, the cell normally is instructed to self-destruct.The theory of carcinogenesis suggests that in certain individuals, an error in DNA copying may not be noticed, the cell cycle may not stop in time for repair, or the

defective cell may not self-destruct. If the DNA error is not identified and corrected, the genetic change becomes a permanent mutation and is passed on to all daughter cells. This step is irreversible and is called cellular initiation. For a cancer to develop from this first, irreversible event, years of additional interactions with the cell by endogenous (internally-produced) and exogenous (environmental) factors

that cause additional genetic changes must occur, and all must lead to the production of a cell that proliferates aggressively and without quality control. These additive effects are called promoting events. Factors that promote the acceleration of the cell cycle and those that allow an abnormal cell to avoid detection by the immune system are most likely to result in a mutated cell becoming carcinogenic.

Promoters of DNA Replication Errors - Certain physical agents and chemicals agents as ionizing radiation, ultraviolet radiation, components of cigarette smoke, aromatic hydrocarbons, certain dyes, nitrosamines (present in preserved meats), and asbestos. - Certain viruses have been identified that can cause DNA mutations as Burkitt's lymphoma, caused by the Epstein-Barr virus,

cervical cancer, caused by certain strains of the human papilloma virus, and liver cancer, caused by the hepatitis B virus. Kaposi's sarcoma occurs especially in those suffering from AIDS.Risk Factors for cancerRisk factors include exposure to any physical, chemical, or viral substance that is known to be mutagenic, and prolonged exposure to any promoter. Mutagens may be inhaled or eaten,

or may act on the skin, such as in the case of ultraviolet (UV) radiation.-Behavioral Risk FactorsBehavioral risk factors include cigarette smoking and diets rich in animal fat and preserved meats. Approximately a third of all cancers in the United States can be attributed to cigarette smoking, and a third to diet. Other environmental factors, include

exposure to asbestos, coal tar and radiation from sunlight.Other behavioral risk factors include those associated with sexual behavior.- Hormonal Risk Factors- Estrogen may act as a promoter for certain cancers, such as breast and endometrial cancer. Because estrogen levels are high in menstruating women, the risk for developing breast cancer is increased in women who started

menstruating early and reached menopause late.- Delayed childbearing or choosing not to bear children increases the risk of breast cancer - Inherited Risk FactorsCertain cancers have a higher tendency to run in families than others. For example, colon and breast cancer .Factors That are Protective Against Cancer Development

- Women who breastfeed for at least 6 consecutive months and who have had multiple pregnancies have a reduced risk of breast cancer.These findings may relate to the decreased number of menstrual periods experienced by these women.- Progesterone appears to be protective against breast cancer by inhibiting the stimulatory effects of estrogen. Progesterone is high

during pregnancy, which may explain why women who have had many pregnancies have a reduced risk of breast cancer. - Dietary factors are important in reducing cancer risk. These substances include vitamins A, E, and C and folic acid, all of which are prevalent in green, leafy and colorful vegetables and fruits.

Clinical Manifestations of cancer

Cachexia is a term used to describe the general wasting of fat and protein seen in many patients with cancer. Anemia occurs for many different reasons and in many different types of cancers. Fatigue frequently occurs as a result of poor nutrition, protein malnutrition, and poor oxygenation of tissues resulting from anemia..

Diagnostic Tools

Diagnosis of cancer involves reviewing the patient's clinical presentation, gaining information on personal habits such as smoking . Screening tests, such as Pap smears to detect cervical cancer, mammograms to detect breast cancer, and digital examinations of the prostate coupled with a blood assay for prostate-specific antigen (PSA). Testing for other cancer

markers may be performed based on suspicion. Advanced methods include radiographs, CAT scans, and magnetic resonance imaging (MRI). Special bone scans may also be used. Cancer diagnosis is confirmed by surgically extracting a sample from a suspicious lesion, a procedure known as a biopsy, and performing a microscopic examination of the cells.

Complications

- Infections develop as a result of protein malnutrition, other dietary deficiencies, and immune suppression . - Pain may occur as a result of the invading tumor pressing on nerves or blood vessels specially in space-limiting compartments, such as bone or brain in the area. Compression of the blood vessels can lead to tissue hypoxia, lactic acid accumulation, or cell

death.Headache is a common manifestation of advanced brain cancer, and bone pain is common with bone cancer at any age. GI pain occurs when the smooth muscle of the gut is stretched.

Treatment

- Surgery has a better chance of curing a cancer if used on solid, well-circumscribed tumors. Tumors that have metastasized may be treated with surgery to give the patient relief from pain.

Surgery is also used to debulk the tumor, which reduces burden and improves the response to chemotherapy or radiotherapy. - Radiation therapy uses ionizing radiation to kill cells primarily by altering the DNA enough that brakes on the cell cycle. Often, radiation is used in addition to surgery to shrink the tumor.

Cancer Therapy

Mode of

Adverse

ActionEffects

Surgery Reduce tumor size to alleviate pain; prevent metastasis if

Pain; deformity

used early; diagnosis

Radiation Damage dividing cells; stimulate apoptosis;

Injures and leads to death of normal cells; bone

halt cell cycle

marrow depression; skin desquamation

Chemotherapy

Multiple actions on cells

Injures and kills normal cells;

to stop progression through cell cycle; may involve combination therapy and

anorexia; nausea; bone marrow depression

may act selectively or nonselectively

Immunotherapy/Biotherapy

Activate host immune syste

Some drugs may cause flu-

m to better recognize and destroy tumor cells; specifically block enzym

like symptoms

es and growth factors required for metastasis;

Chemotherapy uses drugs of several different classes to destroy tumors which grow rapidly and therefore are most susceptible to chemotherapy. However, healthy

cells are also susceptible to the damaging effects of chemotherapy. Chemotherapy is frequently used in addition to surgery or radiation therapy, but may be used alone. It also may be used for palliative purposes. Chemotherapy usually causes bone marrow suppression, which in turn causes fatigue, anemia, bleeding tendencies, and an increased risk of infection. Immunotherapy is a form of cancer treatment that takes

advantage of the two cardinal features of the immune system: specificity and memory. Immunotherapy may be used to identify a tumor and any sites of hidden metastasis. Immunotherapy may stimulate the host's own immune system to respond more aggressively to a tumor, or tumor cells may be attacked by antibodies developed in the laboratory.

Cancer Prevention

- Avoidance of cigarette smoking- A diet rich in fruits, vegetables, and fiber and low in animal fat .- Avoidance of sexually transmitted diseasesCancer Detection- Early cancer detection tests include self breast examination and mammography, prostate examination, self testicular examination, and regular skin examination.

- Some screening tests, including Pap smears, tests for intestinal polyps, and biopsies of abnormal skin lesions.