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A. Oncology is the study of malignant tumors; transformed= cancerous=malignant=neoplastic
1. Transformed cells have abnormal growth patterns
a) They don't have a program for cell death - immortal
b) There is no limit on the number of cell divisions (no Hayflick limit)
c) They have a lower serum dependence than their normal counterparts; i) it was demonstrated that tumor cells secrete their own growth factors;
d) They don't completely differentiate (example - blast cell association with leukemia) or make products usually associated with less differentiated states.
e) They don't show contact inhibition or a density limitation of growth. i) the loss of contact inhibition can be detected by observing the formation of foci of rounded cells or overlapping cells within the regular pattern of normal surrounding cells .
f) They are anchorage independent. i) many of the properties associated with neoplastic transformation are the result of cell surface modifications . One particular protein (LETS) is lost from the surface and contributes to a decrease in cell adhesion; a result of this leads to a disorganized growth pattern and loss of density limitation of growth. Detachment from the tissue in which a tumor arises contributes to the formation of metastases in foreign sites.
g) Tumorgenesis is a trait. i) demonstration of the formation of invasive or metastasizing tumors in a living host animal. Transplanted tumor cells injected into similar species (hosts) will produce tumors in a high proportion of cases while normal cells of a similar origin will not.
h) Proteolytic enzyme production is high. Breakdown of tissue barriers is accomplished by the large quantity of secreted enzymes. An experiment using a chick egg embryo - the CAM - demonstrated the penetration of tumor cells across this barrier. Significant role in metastasis.
i) Tumor angiogenesis factor is secreted. Tumor cells release a factor(s) capable of inducing blood vessel proliferation to the tumor. Anti-angiogenesis drug therapy is a exciting approach to decrease the growth of tumors. An experiment using the CAM and an extract from tumor cells showed the proliferation of blood vessels when compared to an untreated CAM.
j) Their nutrient requirement is lower than normal cells.
k) Their genetic material is unstable/abnormal. Mutation of DNA is the prime cause of neoplastic transformation. Chromosomal abnormalities and variations in DNA content per cell has been noted. There are chromosomal rearrangements - translocations of the long arms of Chromosome 8 and Chromosome 14 are found in Burkitt's lymphoma. A translocation between Chromosome 9 and Chromosome 22 constructs the Philadelphia chromosome marker that distinguished chronic myelogenous leukemia. Small lung cancer has a deletion in Chromosome 3. Note that a mutation in a critical cell cycle control protein will cause a significant deviation of the normal operation of the cell cycle. These abberations constitute tumor specific markers which can be extremely valuable in the confirmation of neoplasia.
These are properties of transformed cells that are found in 'growth characteristics', 'genetic properties', and 'neoplastic properties'
B. Cell Cycle
1. It is the life cycle of the cell. It includes replication of DNA, division of the nucleus, and division of the cytoplasmic contents. Failure of a normal cell cycle leads to cancer
2. In cancer cells , control of the cell cycle can be lost in two ways
a) The cells may be continuously signaled to divide without entering the resting stage of the cell cycle
b) A signal that would have caused normal cells to stop dividing may have been removed.
3. The phases of the cell cycle are:-
S - (synthesis) DNA replication takes place (chromosome duplication)
G1 - (Gap) - cell grows (metabolism increases, RNA and protein synthesis is elevated, organelles duplicate (ie., mitochondria number doubles)
G2 - (Gap) - Preparation stage for CD (initial protein and RNA synthesis increase)
G0 - (Gap) - resting stage
M- (mitosis) - nuclear and cytoplasmic division
4. Normal cell development is the result of tightly controlled cell division, cell growth, cell death (apoptosis). If contol systems fail, so does normal development. Uncontrolled cell division and growth give rise to tumors.
5. Fate of a newly formed tumor cell - a) if it is detected by the immune surveillance system, it will be destroyed. b) if it escapes detection, it will divide to produce a clone of tumor cells that may develop into such a mass that it can't be destroyed (establishment of tumor)
C. "Researchers now understand in detail the processes that lead to cancer
1. Signal: Epidermal growth factor ( EGF ) is a growth factor that will bind only to those cells possessing the EGF receptor on its outer surface. It fits into the receptor like the way a key fits into a lock or a substrate fits into a enzyme.
a) Receptor: Changes in genes that increase the number of receptors on the cell surface amplify the division signal by providing more targets for growth factors (results in uncontrolled cell growth or cancer. More than 20% of breast cancers overproduce receptors for EGF. Herceptin is an exciting new agent used to treat breast cancer. This human-antibody like protein is made via genetic engineering in mice . It binds to the excess receptors on breast cancer cells thereby decreasing the uncontrolled growth signaling.
b) Relay: passage of the divide signal into the cell's interior by a protein called RAS that acts as a relay switch. When activated the shape of RAS changes in a way that it can nowinitiate a chain reaction of the signal to the nucleus. Mutated forms of RAS behave like a relay switch stuck in the ON position, continuously instructing the cell to divide when it should not. 30% of all cancers have a mutant form of RAS.
c) Amplifying the Signal: An activated RAS acts on enzymes called protein kinases which transfers a phosphate group from protein to protein in that chain of amplification (called a cascade). Mutations in any protein kinases can dangerously increase the already amplified signal and lead to cancer. 5% of cancers have a mutant form of protein kinases (usual case involves Src
d) At the Nucleus: unleashing the copy signal. In healthy cells, the primary brake on CD is a tumor suppressor protein, pRB. pRB blocks the signal that directs the cell to copy its DNA. Normal CD is triggered to begin when pRB is inhibited; unleashing the copy signal. Mutations that destroy pRB release the signal from its control completely, leading to ceaseless CD. 40% of all cancers have a defective pRB.
e) Is the DNA okay to copy? : p53 is a tumor suppressor protein. p53 inspects the DNA and when it finds damaged DNA , it stops CD and activates the cell's DNA repair systems. If it isn't repaired in time, p53 causes apoptosis (programmed cell death). More than 50% of all cancers have a disabled p53. 80% of lung cancers. Cigarette smoke contains benzo (a) pyrene that can cause mutation of the p53 gene. It was found the in mice which were missing the p53 gene, that they were prone to multiple tumors. Some cancer-causing viruses make a protein that can bind to p53; if this happens then p53 can't function and tumors form.
f) Life Span of Cell: In healthy cells, another tumor supressor inhibits production of a special enzyme called telomerase. Without this enzyme, a cell's chromosomes lose material from their tips. over time, more of the tip gets lost and after 30 or so CDs, enough is lost and the cell stops dividing and undergoes cell death scenerio. Mutation that destroys this telomerase inhibitor releases the brake, making cancer possible.
D. Types of Cancer and Building up the Vocab.
1. Carcinoma - cancer derived from epithelial cells (carcinomas are most most form of cancer since we are covered with epithelial cells. Basal cell carcinoma - cancer of the surface epithelium ( squamous - deeper location of epithelium). Adenocarcinoma - malignant tumor of the epithelial lining of a gland.
2. sacoma - cancer of connective tissue or muscle cells. Fibrosarcoma - malignant tumor of fibrous tissue
3. Melanoma - cancer of melanin-producing cells of the skin (pigment-producing cells) A mole is a benign tumor but can become malignant and very metastastic.
4. Leukemias - cancer of blood-forming tissue. Includes detection of undifferentiated cells- blasts. Erythroleukemia - leukemia of the RBC lineage. Includes Lymphomas - cancer of the lymphoid tissue - the lymphatic system. Hodgkin's disease. - recall there are drugs that work against Hodgkin's lymphoma at four sites in the cell cycle.
5. Breast milk causes cancer cells to undergo apoptosis. Study from Sweden showed that alpha lac is a dual purpose protein; it helps in the formation of lactose, a milk protein and when in the intestinal system of the baby, it changes shape in the acidic condition and binds to cancer cells if around. Protects a baby who has an immature immune system.