Patho Test 3 Ch 12 Cancer Biology – Flashcards

Age, Strongly tied to Gender, Lifestyle, ethnicity, infections, and genetics

1. Totipotent cells Fertilized Ova is capable of differentiating into any type of cell the human body has.

2. Multipotent cells has eliminated many types of cells by permanently turning off the associated genes. E.g. Endoderm, Mesoderm, Ectoderm cells

3. Pluripotent cells Narrowed down possibilities to a few related cells. Bone Marrow.

4. Unipotent cells Can only for one type of cell, but still retain the properties of a stem cell.

5. Mature differentiated cell. Functional tissue cell, unresponsive to growth factors.

Note: A. Each time a cell divides, each daughter cell has the option of remaining as a stem cell or to irreversibly differentiate into a more mature cell. B. That then involves permanently turning off certain genes, and expressing only those genes pertaining to the specialized mature cell. C. This process involves the stimulation by growth factors, maturation factors and induction by neighboring tissues through cell-cell signal proteins. The cell are regulate by the cells around them.

The biological meaning of the term differentiation denotes the developmental process whereby cells gradually acquire the capacity for a more specialized function by change of phenotype. While developmental biologists generally view this process as unidirectional, observations in the context of cancer show that the differentiation process can reverse and that cells can dedifferentiate.

1. Growth factors (See table 1-6 page 39) 2. Cell-cell communication through gap junctions (contact inhibition) 3. Terminal differentiation (See Fig 11-7 page 371)

(I) Both cells are not differentiated. (II) Both cells proliferate extensively. (III) Both cells self-generate, (in essence, are immortal) (VI) Both are sensitive to radiation therapy. (V) Both can be induced in-vitro to differentiate with the proper differentiation factors.

Tumor classification and nomenclature: Tumor: Abnormal growth due to uncontrolled cell proliferation that serves no function Neoplasm: New growth Benign Tumor: Not referred to as cancers, Growths that are encapsulated and well differentiated, cell retain normal tissue function. Cancer: Now reserved for malignant neoplasms, characterized by rapid growth, loss of differentiation, and a lack of normal tissue organization.

Tumor classification and nomenclature: Tumor: Abnormal growth due to uncontrolled cell proliferation that serves no function

Tumor classification and nomenclature: Neoplasm: New growth

Tumor classification and nomenclature: Benign Tumor: Not referred to as cancers, Growths that are encapsulated and well differentiated, cell retain normal tissue function.

Tumor classification and nomenclature: Cancer: Now reserved for malignant neoplasms, characterized by rapid growth, loss of differentiation, and a lack of normal tissue organization.

Tumor classification and nomenclature: A malignant neoplasm is composed of cells that look less like the normal cell of origin. It has a higher rate of proliferation. It can potentially invade and metastasize.

1. Named after Tissue of origin 2. Benign or malignant (invasivness, Grade ) 3. Degree of differentiation (grade)

Carcinomas ---Epithelial tissue Adenocarcinoma ---Glandular Epithelial Tissue Sarcomas ---Connective tissue leukemias ---Blood forming organs Gliomas ---Glial cells of the CNS Lymphoma ---Lymphatic tissue

Tumor grading Estimates the degree of differentiation or lack thereof of the cancer cells. Cancer Staging: Rating of the cancers invasiveness Grade=configuration of the cell Stage=where gone Increase in the number of grade or stage the worse

Grade I----- Closely resembles tissues of origin., retains some specialized function. Has not invaded the capsule (Benign Neoplasm) Grade II--- Less resemblance, more variation in size and shape, increased mitosis. Has begun to invade the Capsule (Malignant Neoplasm) Grade III----- Does not closely resemble tissue of origin, much variation in size and shape, greatly increased mitosis. ( Poorly differentiated Malignant Neoplasm) Grade IV----- No resemblance to tissue of origin, great variation of size and shape of tumor cells. (Anaplastic Metastatic Neoplasm)

Stage I ------ Cancer is confined to the Organ of Origin. Stage II ------ Cancer is locally invasive, broken through capsule Stage III ----- Cancer has spread to regional structures, e.g local lymph nodes. Stage IV ----- Cancer has spread to distant organs.

Refers to a tumor that is still in the tissue of origin and has not yet invaded or broken through the basement membrane beneath or capsule.

Def: Growth related gene: codes for proteins that control growth and differentiation, but with the right mutation, lead the cell to become cancerous. (See page 374) e.g. 1. Growth factors 2. Growth factor receptors 3. GF Receptor Signal Transducer 4. Nuclear Protein 5. Suppressor Proteins 6. Proteins that regulate Transcription 7. Enzymes that repair damaged DNA

Def: Over-expressed growth stimulating one of two homologous genes. genes: Causing abnormal growth. Overstimulation of these genes cause cancer. Only requires one mutation, acts as a dominant trait.

Def: Genes which inhibit cell growth and division and promotes terminal maturation. Generally we are heterozygous, if both alleles mutate, or become dysfunctional, control of the cell growth and differentiation is lost. Requires two mutations or silencing of the functional gene, Through gene deletion or Epigenetics

Def: "Guardians of the genome" Genes that repair damaged DNA or DNA replication mistakes. When this are dysfunction, the number of mutations increases dramatically

Def: Virus that inserts its DNA into the host cells and causes uncontrolled cell growth and division.

Process by which the cell transforms from the normal shape and function to an abnormal shape with little or no normal function. Includes an enlarged nucleus with nuclear membrane projection and pockets, and chromosome changes.

Cancers cells independence from normal cellular controls.

Loss or absence of differentiation, do not have specialized function or shape. Meaning "without form" Cancerous cells are generally round, with irregular borders, enlarge nucleus. (Dynamics).

Do not need to be anchored to CT or other cells to divide.

Number of cell division is not limited as other cells. Acts as a stem cell.

Mutations Necessary for Normal cells to become Metastatic Cancers cells: (Fig 12-16 Page 380) 1. 1 mutation in an Oncgene, (Responds abnormally to Growth factors). Can be GF, or receptor, or signal cascade to nucleus (e.g RAS mutation) signals cell to grow in the absence of GF.. 2. 2 Mutations in a Tumor Suppressor Gene (decreased responsiveness to mitosis inhibiting and cell differentiation factors) Two mutations in each homologous gene or Epigenetic suppression or Gene deletion 3. Mutation in genes regulating Glycosphingolipids (Increased responsiveness to GF) 4. Mutation disabling the Apoptosis process, Usually TP53 gene (prevent protective cell suicided) 5. Mutation or alteration in genes expressing Telomerase (immortal growth) 6. Mutation in genes involved with the expression of Fibronectin, (Cell Adhesion) Used to anchor the cell to neighboring cells or to surrounding CT. 7. Mutation of genes making or regulating Gap Junctions, loss of contact inhibition. 8. Abnormal secretion of Angiogenic growth factors. (Fig 12-17 page 381)

1. Mutation of proto-oncogene (just one needed). 2. Epigenitic silencing of a tumor suppressor gene (2 silencing OR 1 silence + 1 mutation OR 2 mutations). 3. Downregulation of glycoshingolipids; also downregulates MHC-I, which should induce NK cells to attack. 4. P53 gene inactivation (no apoptosis). 5. Production of telomerase in mature cells (immortal cell growth). 6. Silencing of genes for fibronectin (cell adhesion). 7. Elimination of gap junctions (cancer cells do not communicate). 8. Abnormal secretion of angiogenic growth factor (for tumor vascularization).

Leukemias do not need mutations for: p53 gene silencing (since leukocytes are already free floating, this gene is already silenced). Fibronectin gene silencing (leukocytes do not need to be anchored). Gap junction elimination (leukocytes have no gap junctions for communication). Angiogenic growth factor secretion (leukocytes do not need to be vascularized).

6. Decreased gap junctions: Thought to play a mayor role in cancer development. Many tumors promote, alter or block gap junction function or formation. Blocks Cell-cell communication. Gap junction are either blocked or down-regulated in cancer cells.This implies that there is reduced or absent cell cell communication and decreased contact inhibition by neighboring cells. Gap Junctions can be down regulated by known carcinogenic agents. 2. Changes in Glycoproteins and glycolipids: Decreased communication between cells. May increase immune response to the cancer cells.

3. Loss of Fibronectin: With collagen and elastin, Fibronectin is a cell-surface protein that mediates cellular adhesive interactions., adhesiveness. Protein that form Cadherins and integrins. Which form the adhesion junctions between cells and between the cell and surrounding CT. 4. Secrete Protease: e.g. activates Plasminogen, disrupts extracellular matrix. Decrease adhesiveness. Allows the cancer cells to escape the capsule

P53.

Telomerase

Tumor Cell Markers: (See Table 12-3 Page 369) Def: Substances secreted by the cancer, on tumor cell membranes or released into ECF compartments. Assists in. . . 1. identifying persons at high risk for cancer 2. Diagnose the type of cancer 3. Follow the clinical course of the cancer, effectiveness of treatment. 1. Hormones Ectopic hormones, produced by tumors cells of a non-endocrine origin. ACTH, Catecholamines Immature or fetal forms of a hormone e.g. hCG. AFP etc. 2. Enzymes Immature or fetal types of an enzymes, or in abnormal proportions. 3. Genes Oncgenes, mutated forms. 1. Phophokinases, turnon and off pathways. 2. DNA binding proteins 3. Cellular growth factors. 4. Antigens Production of Neoantigens. Nonself, may assist immune response destroy tumor. Normal antigens: PSA, Prostate Specific Antigen, More cells = 8likelihood of CA 5. Antibodies Ineffectual immunnoglobins, e.g M proteins in multiple myeloma. 6. Proteins: AFP, alpha fetal protein, secreted by liver cancer cells and germ line cancers.

Since cancer needs at least 7 mutations to occur, cancer usually takes place later in life because it takes that long to collect 7 mutations. However, if someone has inherited a mutation (or 3), they don't need to spontaneously mutate as much, so they can be more susceptible to cancer at a younger age. Genetics of Cancer: Cancer is caused by mutations, Inherited, spontaneous or triggered by environmental factors. Environmental factors are called carcinogens or Mutagen. Especially if the mutation occurs in the Caretaker Genes, —> produce proteins that repair damaged DNA —> Leads to increase mutation rate, If damage is severe, then apoptosis should occur.

Causes of uncontrolled cell growth and division: Transformation: Process by which the cell transforms from the normal shape and function to an abnormal shape with little or no normal function. Includes an enlarged nucleus with nuclear membrane projection and pockets, and chromosome changes. Autonomy: Cancers cells independence from normal cellular controls. Anaplasia: Loss or absence of differentiation, do not have specialized function or shape. Meaning "without form" Cancerous cells are generally round, with irregular borders, enlarge nucleus. (Dynamics). Anchorage Independence: Do not need to be anchored to CT or other cells to divide. Immortality: Number of cell division is not limited as other cells. Acts as a stem cell. maybe need more....

Oncotic Viruses: Papillomavirus: Vaginal warts and Virtually All cervical CA's Hepatitis B & C Viruses, Liver adenomas Adeno-viruses Epstein Barr Virus —> B cell lymphoma Herpes Viruses HIV Human T cell Leukemia Lymphoma Virus Mechanism of Viral Mutagenesis: (a) Direct mutagenesis of Proto- Oncgenes. (b) Insertion Mutagenesis at specific sites: their own oncogenes V onc Leads to the activation of V-onc or the cells own C onc genes. (c) Indirect— cause rapid cell proliferation, which are more subject to spontaneous mutation. Cervical and Liver Cancers account for 80% of viral linked cancers.

Complications of Cancer and Cancer Therapies: (See box 12-2 Page 396) 1. Para-neoplastic syndromes (See table 12-11 page 395) Some tumors release hormones, acting as ectopic sources. They do not respond to negative feedback controls. Hence hyper secretion syndromes. E.g Serotonin, flushing, diarrhea, and wheezing. 2. Pain initially little or no pain, but is present in 60-80% of terminally ill cancer patients Cause: a. Pressure b. Bowel or blood flow obstruction (ischemia) c. Stretching of viscera (abdominal) d. Tissue destruction. (Bone) e. Inflammation and Kinin & cytokine release. 3. Fatigue Most frequently reported symptom of cancer and cancer treatment. Described as a lack of energy, lethargy, depression, inability to concentrate Causes: a. Sleep disturbances b. Biochemical changes, cytokines, 9 neurotransmitter . c. Nutritional status Muscle loss d. Anemia 4. Cachexia (See fig 11-27 page 390) wasting away of lean body mass, may have to do with the stress response. Increase sympathetic stimulation and cortisol. Causes: multiple:1. Anorexia— pain, depression, chemotherapy, alterations in taste. High blood glucose & blood fat levels, trigger satiation 2. Poor use of glucose 3. Decrease insulin secretion, (epi ->â?) 4. Increased catabolism of proteins, increased blood AA's Cortisol? 5. Decreased peristalsis. (epi ->â?) 6. Increased triglyceride hydrolysis (epi ->â?) 7. Aversion to red meat 5. Anemia Three general mechanisms that cause anemia in cancer. 1. Chronic bleeding due to tissue disruption. 2. Medical therapies, e.g. chemotherapy. 3. Malignancy in hemopoietic tissues. 4. Malnutrition 6. Leukopenia and Thrombocytopenia Loss of WBC's and platelets. Causes: 1. Chemotherapy. 2. Malignancy in hemopoietic tissues. 7. Infection 1. Reduction of immune system components 2. Loss of Gut barrier, -> invasion by normal flora, Due to a. GI tumor b. Chemotherapy 8. GI complications 1. Loss of Gut barrier due to decrease cell replacement (Chemo), 2. Loss of absorption surface area ...Mal-absorption. 3. Diarrhea, 4. Sepsis from loss of Gut barrier. 9. Alopecia, (hair loss) Usually temporary.

Multi Steps of Metastasis: (See fig 11-21 page 381) 1. Local invasion (see above) 2. Penetration into blood vessels or lymphatic or both 3. Release into the lymph or blood 4. Transport to a secondary site by blood or lymph or both 5. Arrest, adherence, and proliferation at the secondary site. 6. Neovascularization, Secretion of VEGF and PDGF to stimulate new vessel growth to deliver nutrients to sustain the tumor. Note 1: The most common route for distant metastasis is through lymph and Note 2: The success of the cancer cells is greater if clusters of malignant cells release and adhere together or they cluster with platelets. Note 3: Cancer cells found in the lymph nodes are usually the first clinical evidence that metastasis has occurred. (See fig 11-25 page 386) Note 4: Lymph nodes may act as a barrier to metastasis for a period of time until secondary local invasion cause another release from the lymph nodes. Metastasis to distant organs A Loss of cell adhesion and migration lead to the movement of cancer cells into circulation and/or lymph vessels They will go to: (see Fig 12-19, page 385 and Fig 12-20 & 12-21 page 389) B. First capillary bed encountered, e.g. Lungs, Liver, kidney, etc. C. Organ Trophism, (See 12-24 page 392) Tumors are heterogenous, and individual cells are attracted to certain organs or tissues. Those organs either secrete chemotaxic chemical or cancer cells show preferential adherence to tissue receptors of the

Immunologic Defense against tumors A. If tumor cell express a tumor specific antigen. The immune system will reject the tumor. Targeted by Tc cells. B. Immunologically depressed individuals have a greater risk of tumor development. Mechanism: A. If B lymphocytes are activated, then it usually is a tumor specific antibody. (TSA) Two ways to kill a cancer cells with a TSA. 1. Activate complement 2. Antibody dependent cell-mediated cytotoxicity. (ADCC) Fc portions bind to the membrane of . . . A. Monocytes, B. Neutrophils C. B cells D. Certain null cells called killer cells. Allows cells to recognize the cancer cells. B. Natural Killer cells First line of defense against cancer cells. Activated with Chromosomal changes or Activated when MHC Type I down regulates. C. Cytotoxic T cells: Most effective defense for tumor rejection. 1. Attack TSA antigens. Tumor Specific Antigens are endogenous, displayed on MHC Type I 2. Differentiation stimulated by presentation of the TSA by macrophages. 3. Activated by Helper T cells.

Cell surface changes in cancer cells and their functional importance: 1. Decrease in Glycosphingolipids: Normal effect: Decreases cell responsiveness to grow factors. Cancer: Decrease Glycosphingolipids, possibly increase the cells responsiveness to growth factors. 2. Changes in Glycoproteins and glycolipids: Decreased communication between cells. May increase immune response to the cancer cells. 3. Loss of Fibronectin: With collagen and elastin, Fibronectin is a cell-surface protein that mediates cellular adhesive interactions., adhesiveness. Protein that form Cadherins and integrins. Which form the adhesion junctions between cells and between the cell and surrounding CT. 4. Secrete Protease: e.g. activates Plasminogen, disrupts extracellular matrix. Decrease adhesiveness. Allows the cancer cells to escape the capsule 5. Decreased Anchorage Proteins: Desmosomes, Adherens, junctions. Normal cells need to be anchored to undergo mitosis, Cancer cells undergo anchorage independent mitosis. This also allows them to metastasize. This is linked to changes in Fibronectin 6. Decreased gap junctions: Thought to play a mayor role in cancer development. Many tumors promote, alter or block gap junction function or formation. Blocks Cell-cell communication. Gap junction are either blocked or down-regulated in cancer cells.This implies that there is reduced or absent cellcell communication and decreased contact inhibition by neighboring cells. Gap Junctions can be down regulated by known carcinogenic agents. Note: All of above changes alter the cell's ability to communication with the community of cells it should be apart of. This leads to Destiny independent growth in transformed cells Note: Normal cells prevent the development of blood vessels by secreting Thrombospondin. Tumor cells may not secrete thrombospondin. Successful tumors are capable of manipulating the inflammatory and immune responses to Phenotypes associated with healing and growth factors rather than destructive .

Chemotherapy: 1. Kills cells that are active in mitosis or are capable of mitosis. Hopefully the chemo eradicates enough cells that the body can kill the rest. E.g Methotrexate, L-asparaginase, cyclophosphamide, anthracyclines 2. Combinations of different types of chemical agents have been the most successful. Each drug attacks the tumor cells at a specific weakness. 75 - 80% long term remission or cure rates. 3. Some cells in Tumor mass may be resistant Surgery: Objective: 1. Remove the whole tumor before it metastasizes. 2. Preventative Surgery, e.g Mastectomy 2. Remove the pressure to: A. alleviate pain., not intent to cure. B. Debulk prior to chemotherapy C. Determine Staging, Nodal involvement indicating spread Radiation: Focuses on only the tumor and hopefully doesn't damage too severely the tissue around it. Damages or destroys large macromolecules like DNA. Immunotherapy: Advantage: 1. Selectively Kill tumor cells, while sparing normal cells. 2. Memory cells for prevention of emergence of primary tumor BCG Bacterial wall extracts are injected into tumor, Activates macrophages and NK cells Some success with Urogenital and Lung CA DNCB Dinitrochlorobenzene Body first sensitized, then DNCB is painted on Skin tumor, Causes Hypersensitivity response e.g (Type IV) similar to poison Ivy LAK (Lymphokine Activated Killer) cell therapy Cultured Tc cells in IL-2 activated against TSA (Tumor specific Antigens) LAK cells reinserted into patient, cause lysis of tumor cells Used successfully against melanoma and Renal cell carcinoma Monoclonal Antibodies: 1. Used to diagnose and monitor treatment results 2. Goal: to mediate tumor rejection, 3. Has been most successful against hematologic and Lymphatic cancers 4. Conjugated Antibodies, attach radioactive isotopes or toxins, when antibodies bind to tumor cells, they kill target selectively as with radioactive iodine with Thyroid cancer Alternative Therapies: "Rarely is there evidence that they are medically effective"!

Chemotherapy: 1. Kills cells that are active in mitosis or are capable of mitosis. Hopefully the chemo eradicates enough cells that the body can kill the rest. E.g Methotrexate, L-asparaginase, cyclophosphamide, anthracyclines 2. Combinations of different types of chemical agents have been the most successful. Each drug attacks the tumor cells at a specific weakness. 75 - 80% long term remission or cure rates. 3. Some cells in Tumor mass may be resistant

Surgery: Objective: 1. Remove the whole tumor before it metastasizes. 2. Preventative Surgery, e.g Mastectomy 2. Remove the pressure to: A. alleviate pain., not intent to cure. B. Debulk prior to chemotherapy C. Determine Staging, Nodal involvement indicating spread

DNCB Dinitrochlorobenzene Body first sensitized, then DNCB is painted on Skin tumor, Causes Hypersensitivity response e.g (Type IV) similar to poison Ivy

Radiation: Focuses on only the tumor and hopefully doesn't damage too severely the tissue around it. Damages or destroys large macromolecules like DNA.

Immunotherapy: Advantage: 1. Selectively Kill tumor cells, while sparing normal cells. 2. Memory cells for prevention of emergence of primary tumor Alternative Therapies: "Rarely is there evidence that they are medically effective"!

LAK (Lymphokine Activated Killer) cell therapy Cultured Tc cells in IL-2 activated against TSA (Tumor specific Antigens) LAK cells reinserted into patient, cause lysis of tumor cells Used successfully against melanoma and Renal cell carcinoma

BCG Bacterial wall extracts are injected into tumor, Activates macrophages and NK cells Some success with Urogenital and Lung CA

Monoclonal Antibodies: 1. Used to diagnose and monitor treatment results 2. Goal: to mediate tumor rejection, 3. Has been most successful against hematologic and Lymphatic cancers 4. Conjugated Antibodies, attach radioactive isotopes or toxins, when antibodies bind to tumor cells, they kill target selectively as with radioactive iodine with Thyroid cancer