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Week 1 - Biology of Cancer

What is cancer caused by?

The malfunction or mutation of genes involved in cell division and cell proliferation.

2 Mutational Routes

Stimulation and Inhibition

Stimulation

Leads to tumor formation - oncogene.

Inhibition

Causes inactivity.

Oncogene

A gene with the potential to cause cancer.

2 Properties that define Cancer Cells

Autonomy and Anaplasia

Autonomy

Cancer cells act independently from normal cell functions.

Anaplasia

Loss of differentiation. Cancer cells lose its ability to function normally, control growth, and control division.

Transformation

Process by which a normal cell becomes a cancerous cell.

Tumor Grading

Estimates differentiation of cancer cells. 4 Grades.

Grade I

Well differentiated. Tumor closely resembles the tissue of origin and retains some specialized function.

Grade II

Moderately differentiated. Tumor has less resemblance to tissue of origin. More variation in size and shape of tumor cells; increased mitoses.

Grade III

Poorly to very poorly differentiated. Tumor does not closely resemble tissue of origin. Much variation in size and shape of tumor cells; greatly increased mitoses.

Grade IV

Very poorly differentiated. Tumor has no resemblance to the tissue of origin. Great variation in size and shape of tumor cells.

Cell Differentiation

Proliferation cells are transformed into different and more specialized cell types, which determines the microscopic characteristics of the cell, function, and lifespan. Adult cell has all its specific sets of characteristics and can no longer divide.

Benign Neoplasms

Benign tumor that has lost its ability to suppress the genetic program for cell replication but retain normal cellular differentiation.

Benign Neoplasms grow by:

Expansion, not infiltration.

Benign Neoplasm Properties

Capsule is mark of demarcation. Usually do not cause death. Known to secrete abnormal hormones.

Malignant Neoplasms

Destructive tumors that grow rapidly, spread widely, and tend to cause death. Robs normal tissue from blood, nutrients, space, and release enzymes and toxins that destroy themselves and other tissues.

Destructive nature of Malignant Neoplasms due to:

Lack of cell differentiation, cell characteristics, rate of growth, and ability to spread and metastasize.

Tumors are classified on the basis of:

Tissue of origin, malignancy, degree of differentiation, and anatomic site.

Carcinomas

Cancers of epithelial tissues.

Sarcomas

Cancers of connective tissues.

Lymphomas

Cancers of lymphatic tissues.

Gliomas

Cancers cells involving the glial cells of the CNS.

Leukemias

Cancer of the blood-forming organs (primarily bone marrow).

7 Standard Features of Cancer Cells

Local increase in cell #, loss of normal arrangement of cells, variations in cell shape and size, increased nuclear size, increase in total DNA, increase in mitotic activity, abnormal mitoses and chromosomes.

Cancer Cell-Surface Changes: Decrease in Glycoproteins and Glycolipids.

Altered receptor density or configuration of the cell surface. Decreased communication and cell signaling. May enhance the immune defense against cancer.

Cancer Cell-Surface Changes: Protease

Cancer cells secrete plaminogen-activation factor which activates protease. Protease activation is needed before the expression of a malignant cell can be changed.

Cancer Cell-Surface Changes: Altered Anchoring Junctions

Normal cells cannot divide or proliferate unless they are anchored. Cancer cells exhibit anchorage independence. Allows cells to metastasize.

Cancer Cell-Surface Changes: Altered Gap Junctions

Tumors block gap junctions which regulate metabolic communication between cells.

Gap Junctions

Allow ions and small water-soluble molecules to pass from the cytoplasm of one cell to the cytoplasm of another cell.

Tumor Cell Markers

Substances produced by cancer cells that are found on tumor plasma membranes or in the blood, spinal fluid, or urine.

3 Uses of Tumor Cell Markers

Screen and identify those at high risk for cancer.
Help diagnose the specific type of tumor.
Observe clinical course of cancer.

Tumor Cell Markers: Hormones

Some tumors produce excess hormones. hCG (human chorionic gonadotropin) is one of the best tumor markers.

Adrenocorticoptropic Hormone (ACTH)

Lung Cancer or Pituitary Cancer hormone tumor cell marker.

Antidiuretic Hormone (ADH)

Lung Cancer hormone tumor cell marker.

Tumor Cell Markers: Enzymes

Expressed in the circulation when the tumor is very large or widespread metastasis has occurred.

Tumor Cell Markers: Genes

Presence of chromosomes or oncogenes inside the cell. (Ph1)

Philadelphia Chromosome (Ph1)

First chromosome marker identified. Present in 95% of patients with chronic myelocytic leukemia.

Tumor Cell Markers: Antigens

Expressed as a result of reactivation of genes turned off at the end of fetal development. Elevated levels of prostate specific antigen (PSA) or alpha fetoproetein.

Carcinoembronic Antigen (CEA)

Tumor cell maker with elevated serum levels found in patients with colon, pancreatic, and breast cancers.

Causes of Cancer

Gene-environment interaction, Inherited genes, Oncogenic viruses.

Causes of Cancer: Gene-environment Interaction

Environmental agents cause cancer by increasing frequency of mutations such as cigarette smoke, carcinogens, x-rays, and UV light.

Causes of Cancer: Inherited Genes

Certain oncogenes can be inherited such as Retinoblastoma (childhood cancer of the eye), Wilms tumor (childhood cancer of the kidney), and breast cancer.

Causes of Cancer: Oncogenic Viruses

Cancer causing viruses that cause a specific type of malignant or benign tumor in susceptible individuals. Divided into 2 groups by nucleic acid: RNA and DNA viruses.

3 Main Types of Oncogenic DNA Viruses

1. Papovaviruses
2. Adenoviruses
3. Herpes-viruses

Cancer of the Cervix and Hepatocellular carcinoma account for:

80% of virus linked cancer.

Risk factor for Hepatocellular Carcinoma

Hepatitis B.

2 Other Viruses Implicated as Causing Cancer

1. Human Immunodeficiency Virus (HIV) - associated with B-cell lymphoma or Kaposi Sarcoma (rare form of blood vessel cancer in the skin).
2. Herpes Simplex Virus (HSV) - associated with anogenital and oral cancers.

Carcinogenesis

The process of tumor development.

Cancer Development Stages (3)

1. Initiation - Causes irreversible changes to DNA after exposure to a carcinogen.
2. Promotion - Initiated cells become cancerous.
3. Progression - Cells become more biologically defective.

Environmental Risk Factors for Cancer

Tobacco use, dietary sources of carcinogens (charbroiled beef), nitrates in fish and meat, low fiber diets, polyunsaturated fatty acids yield free radicals that are toxic, alcohol, obesity, sexual behavior, air pollution, occupation (asbestos), UV radiation, and Ionizing radiation.

Cigarette Smoke Factor

Most important cause of lung cancer. Increases incidence of cancer of the bladder, pancreas, and to a lesser extent kidneys, larynx, oral cavity, and esophagus.

Diet Risk Factors

Nitrates in fish and meat increase risk of gastric cancer. Certain ingested fats increase bile acids and cholesterol metabolites in feces increasing risk of colorectal cancer. Low fiber increase colon cancer risk.

Omega-3 and Selenium-containing Enzymes

Decrease the number and size of tumors (03) and cause destruction of free radicals (SE). SE also decrease mortality from lung, colon, rectal, and prostate cancers.

Alcohol Risk Factors

Increase risk for cancer of mouth, pharynx, larynx, esophagus, liver especially when combine with smoking.

Sexual Behavior Risk Factors

Increased risk of cervical cancer is related to age of first sexual encounter and # of partners. HPV virus (most common cause for abnormal pap smears).

UV Radiation Risk Factors

Basal cell and squamous carcinoma risk increased. Melanoma.

Ionizing Radiation Risk Factors

Emissions from x-rays inhibits cell division and causes alterations in DNA. Can cause leukemias and solid tumors of thyroid, breast, and salivary glands.

Air and Occupation Risk Factors

Air: Radon increases risk of lung cancer.
O: Asbestos exposure accounts for largest number of occupational cancer of the lungs. Manufacturing of dye, rubber, paint, and aromatic amines cause bladder cancer.

4 Type of Cancers occur in Hormone Responsive Tissues

Breast, Endometrium, Ovary, Prostate.

Research on Hormones and Caner focuses on:

The direct actions of the sex steroids (estrogen, testosterone, and progesterone).

Proliferation

Process of cell division. Adaptive mechanism for replacing body cells.

Differentiation

Process of specialization where by new cells acquire the structure and function of the ones they replace.

Doubling Time

The amount of time it takes a mass to double its cell population.

Cells That Do Not Proliferate or Divide

Well-differentiated neurons, skeletal cells, and cardiac muscle cells.

Parent Cells

Continue to divide and reproduce. (blood, skin, liver cells)

Undifferentiated Stem Cells

Cells that can enter the cell cycle and produce large numbers of parent cells when the need arises.

Tumor Spread

Direct invasion of contiguous organs or local spread.
Metastases to distant organs by lymphatics and veins.
Metastases through implantation.

3 Step Sequence of Tumor Invasion

Attachment, Degradation, and Locomotion

Tumor Invasion: Attachment

Step 1. The tumor cell attaches to extracellular matrix and receptors on the tumor bind to pars to the basement membrane of the extracellular matrix.

Tumor Invasion: Degradation

Step 2. The tumor cell releases proteases which break down the matrix.

Tumor Invasion: Locomotion

Step 3. Migration of the tumor cell through the degraded basement membrane. Enables the tumor to spread from the blood vessel into interstitial tissue.

Metastasis

Spread of cancer cells from primary site of origin to distant site. The challenge of reducing cancer mortality is to control this.

3 Mechanisms of Metastasis

Direct or Continuous Extension
Lymphatic Spread
Bloodstream Dissemination

Continuous Extension

Metastasis in which tumors extend into several areas without breaking from the parent tumor which include tissue spaces, lymph and blood vessels, body cavities, and cerebrospinal spaces.

Lymphatic Spread

Metastasis by lymphatics involving the invasion and penetration of tumor cells into lymphatics. Tumor cells carried to the lymph nodes. Often, a mass in the region lymph node is evidence of this metastasis.

Bloodstream Dissemination

Metastasis that is complex and requires tumor cells to detach from blood vessels and spread to distant organs. Involves getting past host defenses, surviving the mechanical trauma of the bloodstream, and lodge in the vascular bed of the target organ.

Frequent Sites of Distant Metastasis

Lung - multiple including brain
Colorectal - liver, lungs
Testicular - lungs, liver
Prostate - bones, lungs, liver, endocrine glands, CNS
Breast - skeleton, lungs
Head and Neck - lymphatics, liver, bone
Ovarian - peritoneal surfaces, diaphragm, liver

Cachexia

Wasting syndrome. Most severe form of malnutrition. Progressive weight loss despite normal intake.

Leukopenia

Decrease in white blood cell count.

Thrombocytopenia

Abnormally low platelets.

Symptoms of Cancer

Pain, fatigue, cachexia, anemia, leukopenia, infection, thrombocytopenia.

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