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39 Cards in this Set
- Front
- Back
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What are specific factors in APOPTOSIS?
A) TRIGGERS: B) MODULATORS: C) EFFECTORS: D) SUBSTRATES: |
A) TRIGGERS:
-Chemo, XRT, hypoxia, -Genetic damage -GF or cytokine withdrawal -Loss of cohesion/adhesion B) MODULATORS: - Many factors/pathways - Bcl-2/Bax family C) EFFECTORS: - Caspase cascade D) SUBSTRATES: - DNA, cytoskeleton |
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How do tumors evade APOPTOSIS? (3)
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1) DYSREGULATION OF ANTI-APOPTOTIC SIGNALS
- 80% of follicular lymphomas have a t(14:18) chromosomal translocation which results in overexpression of bcl-2 - lymphocytes fail to undergo normal apoptotic cell death in lymphoid follicles 2) LOSS OF PRO-APOPTOTIC SIGNALS - Cells that have lost or inactivated proteins involved with apoptosis signaling pathways (PTEN, p53, Bax) are defective in triggering this important homeostatic mechanism - Independence from survival factors 3) IMPLICATIONS FOR THERAPY - Mutations in apoptotic pathway proteins result in resistance to chemotherapy and radiotherapy - Currently, the most curable cancers are those which p53 is NOT mutated |
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* LIMITLESS REPLICATIVE POTENTIAL *
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What is SENESCENCE and IMMORTALIZATION?
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1) Cells in culture have a finite replicative potential
2) After certain number of doublings (60-70), cells stop growing: “senescence.” 2) Senescence can be circumvented by disabling pRb and p53 3) Then, cells continue multiplying until enter: “crisis.” - “massive cell death, karyotypic disarray,end-to-end fusion of chromosomes 4) Occasionally, there is the emercence of a variant (1 in 107) cell that has acquired the ability to multiply without limit: “immortalization”. |
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1) What part of the chromosome helps "count" the number of times it has divided?
2) How are replicative generations counted by? 3) What is the progressive shortening of the telomeres due to? 4) What does their erosion eventually cause? 5) What happens to unprotected chromosomal ends? 6) What does karyotypic disarray lead to? |
1) Counting device: telomeres (end of chromosomes) length.
- Every chromosome bracketed by several thousand repeats of a short 6 bp sequence element. 2) Replicative generations are counted by the 50–100 bp loss of telomeric DNA from the ends of every chromosome during each cell cycle. 3) progressive shortening attributed to inability of DNA polymerases to completely replicate the 3’ ends of chromosomal DNA during each S phase. 4) Erosion of telomeres eventually causes them to lose ability to protect the ends of chromosomal DNA. 5) unprotected chromosomal ends participate in end-to-end chromosomal fusions 6) karyotypic disarray associated with crisis, death of the affected cell |
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1) Where is TELOMERASE most present?
2) What do high levels of TELOMERASE indicate? 3) What does it mean if a malignant neoplasm lacks detectable TELOMERASE ACTIVITY? |
1) Telomerase is not present in most normal cells
- Except for germ cells and stem cells 2) Telomerase levels are generally higher in malignant than in benign neoplasms 3) But― some malignant neoplasms lack detectable telomerase activity Suggests alternate mechanisms of telomere stabilization or lengthening |
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* ANGIOGENESIS *
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Why is ANGIOGENESIS important?
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It is important because in order for tumors to grow >1mm, they MUST induce an accompanying blood supply
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What is ANGIOGENSIS dependent on?
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It is dependent on the local ratio of ANGIOGENIC INDUCERS (VEGF) to ANTI-ANGIOGENIC AGENTS
Normally the ratio is low- no vascular proliferation |
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What are PHYSIOLOGIC and PATHOLOGIC conditions that might turn the ANGIOGENIC SWITCH on?
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PHYSIOLOGIC CIRCUMSTANCES:
- Wound healing - Normal development - Physiologic hyperplasia PATHOLOGIC CONDITIONS - Tumorigenesis - Subclone develops ability to stimulate angiogenesis due to - clonal progression |
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What may inhibit ANGIOGENESIS?
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“The removal of certain tumors e.g., breast carcinomas, colon carcinomas, and osteogenic sarcomas can be followed by rapid growth of distant metastases, and primary tumors can suppress metastases from different types of tumors (e.g., a breast cancer can inhibit melanoma metastases)”
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What are specific examples of ANGIOGENESIS INHIBITORS?
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1) Angiostatin
38 kD internal fragment of plasminogen, from Lewis lung carcinoma 2) Endostatin 20 kD internal fragment of collagen XVIII, from a murine vascular tumor |
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What is the function of ANTI- ANGIOGENIC THERAPY?
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1) Anti-angiogenic agents combined with low dose standard cytotoxic therapy target endothelial cells, not tumor cells
- Tumors regressed to dormant microscopic lesions by endostatin treatment - Tumors cells were proliferating (no cytotoxicity) - There was a high rate of apoptosis in tumor cells - Minimal side effects (low dosage) Synthetic inhibitors, peptides, or antibodies designed to interfere with various steps in the angiogenic process include: - Integrin αvß3 antagonists - metalloproteinase inhibitors |
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* INVASION AND METASTASIS *
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What does it mean to METASTASIZE?
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What are the steps involved in the process of METASTASIS?
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1) DETACHMENT AND DECREASED CELLULAR ADHESION
2) MATRIX DEGRANULATION: MATRIX METALLOPROTEASES: TMPs 3) CELL MATRIX ATTACHMENTS: INTEGRINS 4) ANGIOGENESIS 5) MOTILITY 6) VASCULAR EXTRAVASATION 7) AVOIDING IMMUNE SURVEILLANCE 8) SURVIVE AND PROLIFERATE IN A NEW AND FOREIGN MICROENVIRONMENT |
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1) DETACHMENT AND DECREASED CELLULAR ADHESION: CADHERINS
What is the function of CADHERINS? What are related cytoplasmic proteins? What do signaling pathways regulate? What does the loss of CADHERINS correlate with? |
1) Mediate homotypic cell–cell interactions at adherens junctions
2) Complexed with cytoskeleton via a family of cytoplasmic proteins (α, β and γ-catenin) 3) Signaling pathways regulate cell proliferation, apoptosis, differentiation, and cell motility 4) Loss of cadherins correlates with increased invasiveness and metastatic potential |
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3) CELL MATRIX ATTACHMENTS: INTEGRINS
What do focal adhesion kinase pathways regulate? How do tumor cells alter INTEGRIN EXPRESSION patterns via "INTEGRIN SWITCHING"? |
1) Focal adhesion kinase pathways regulate apoptosis, proliferation, and cell motility
2) Tumor cells alter integrin expression patterns “Integrin switching” - Decreased adhesion to BM - Increased adhesion to ECM - Increased migration over ECM |
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2) MATRIX DEGRANULATION: MATRIX METALLOPROTEASES: TMPs
How does matrix degradation occur? What proteolytic enzymes must they secrete? What do they down regulate? |
1) Tumor cells must destroy the local basement membrane and ECM in order to invade the underlying stroma
2) Secrete proteolytic enzymes Matrix metalloproteinases (MMPs), Collagenases 3) Down-regulate expression of Tissue Inhibitors of MetalloProteinases (TIMPs) |
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4) ANGIOGENESIS:
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5) MOTILITY
What is the migration of tumor cells directed by? What are the two types of factors that may facilitate motility? |
1) Migration: Directed by factors that regulate tumor cell adhesion and cytoskeleton activity
2) DIFFERENT FACTORS AFFECTING MOTILITY: A) Autocrine and Paracrine factors: - Growth factors (IGFs, FGFs, TGF-β) stimulate tumor cell motility - Hepatocyte growth factor/scatter factor: Ligand for the c-met proto-oncogene - Cytokines (Interleukin-8, Histamine) B) Extracellular matrix factors: - Intact ECM molecules (vitronectin, fibronectin, laminin, type I collagen) - Fragments of ECM molecules released from the matrix by MMPs |
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6) SURVIVAL, ADHERANCE, AND VASCULAR EXTRAVASATION
How do tumor cells survive and adhere to other cells/ tissues? What is responsible for adhesion to vascular basement membrane? |
1) Tumor cell interactions with fibrin, platelets, and clotting factors
- Protect tumor cells in circulation from both immune and non-immune destruction (resistance to killing by host monocytes/macrophages, Natural Killer cells, and activated T-cells) - Facilitates attachment to endothelial cells 2) Integrins are probably responsible for adhesion to vascular basement membrane |
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7) AVOIDING IMMUNE SURVEILLANCE
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8) SURVIVE AND PROLIFERATE IN A NEW AND FOREIGN MICROENVIRONMENT
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1) Distribution of metastases varies widely depending on the histologic type and anatomic location of the primary tumor
2) Mechanical factors (James Ewing; 1928) - Most frequent location of distant metastases is first capillary bed encountered by tumor cells - Usually lung and liver – extensive vascular beds; slow-flow 3) Above not always the case…some primary tumors preferentially metastasize to particular sites - Predilection of breast and prostate cancers for bone |
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How is metastasis angiogenesis dependent?
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1) Immature and developing neovasculature is leaky and discontinuous
- Enables tumor cells to enter microcirculation 2) Experimental model: malignant human keratinocytes growing in nude mice - Functional inactivation of VEGF-R by a blocking antibody disrupted ongoing angiogenesis and prevented invasion of malignant cells without reducing cell proliferation - Functional reversion of a malignant to a benign phenotype by inhibiting angiogenesis |
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What is the SOIL AND SEED HYPOTHESIS?
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1) Distant site may have a receptor or binding site for a protein on the surface of the tumor cell that acts as a homing mechanism
2) Chemokines activate cell signaling pathways that support the metastatic focus. |
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How is metastasis a THERAPEUTIC TARGET? (3)
1) Anti-adhesive Agents: 2) Matrix Metalloproteinase Inhibitors: 3) Anti-motility Agents: |
1) Anti-adhesive Agents:
- Peptidomimetics and monoclonal antibodies targeted at integrins. - Antagonists of αvβ3 (Vitaxin) induce vascular cell apoptosis and inhibit angiogenesis by blocking endothelial cell-matrix interactions 2) Matrix Metalloproteinase Inhibitors: - Blocks degradation of matrix, blocks activation of proteases, growth factors - Anti-invasive properties in vitro and anti-angiogenic properties in vivo 3) Anti-motility Agents: - Taxanes block microtubule cycling - Inhibitor of calcium influx (carboxyamido-triazole) |
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* MONOCLONALITY AND CLONAL EVOLUTION/ CLONAL PROGRESSION *
(5) |
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What are the mutations that are required for the development of cancer?
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- Mutations arising in early stages of tumor development are expected to be present in later stages, and each successive stage is marked by additional mutations.
- By isolating precursor lesions, one can map mutations that occur in each of the morphological stages (next slide) |
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What are steps involved in the development of cancer? (4)
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1) Benign tissue surrounding the malignant tissue frequently contains many of the same set of mutations found in the tumor, but lacks at least one mutation that is found in tumor tissue.
2) Certain genes have a high probability of mutating at specific definable stages of colon cancer progression. 2) Loss of the tumor-suppressor gene APC occurs early in the process of transformation, converting colonic epithelial cells to a hyperproliferative state. 3) Hypomethylation of DNA then occurs in the early adenoma stage, followed by activation of the oncogene Ki-ras in carcinoma in situ. 4) A proposed tumor-suppressor gene DCC on chromosome 18q and p53 are lost later in the disease, with the eventual development of a metastatic colon cancer. |
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* EPIGENETICS OF CANCER *
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What is a GENETIC CHANGE?
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This is an ALTERATION in the cell's DNA sequence
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What is an EPIGENETIC CHANGE?
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This is a heritable modification of the genome that does not involve a change in the DNA sequence
- In contrast to classical genetics, epigenetic mechanisms are REVERSABLE, act over a large distance, and usually result in GENE SILENCING |
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What is the result of DNA METHYLATION?
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This is the best method of epigenetic change. It's when methylation of cytosine residues in CpG islands around the gene promoters down- regulate gene expression.
In malignant cells, there are vast areas of hypomethylation, with foci of hypermethylation around TSGs. Microarray- based assays can detect patterns of methylation which not only correlate to tumor type, but also to tumor stage, aggressiveness, and drug responsiveness. |
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What are the implications for therapy?
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Reversal of epigenetic changes has enormous potential for cancer therapy...
Inhibitors of DNA methylation have been shown to induce terminal differentiation and inhibit the growth of several types of tumors in laboratory models. |
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What is DIFFERENTIATION THERAPY?
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Tumor cells are often unable to fully differentiate
Abnormal development in myeloid leukemia cells can be reprogrammed by the appropriate differentiation- inducing cytokines Therapy could be target cell specific and less toxic than standard chemotherapy Development of differentiation inducing agents to treat cancer has been limited to date |
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Acute Promyelocytic Leukemia (APML)
All- Transretinoic Acid (ATRA) |
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Why is it important to study the MOLECULAR aspects of cancer?
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It's important so we can develop therapies that target deranged molecular pathways and signals, instead of reling on traditional chemotherapy and/ or radiation therapy.
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What are specific MOLECULAR THERAPEUTICS?
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1) SPECIFIC ANTAGONISTS OF LIGAND- RECEPTOR INTERACTIONS
2) CYTOTOXIC MONOCLONAL ANTIBODIES 3) TAIONAL MOLECULAR THERAPY TARGETING ONCOGENE PRODUCTS 4) ANTISENSE OLIGODEOXYNUCLEOTIDES 5) DIFFERENTIATION THERAPY |
