Ch 7 Carcinogenesis

Carcinogenesis
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Terms in this set (29)
Carcinogenesis
Process by which normal cells are transformed into cancer cells: Starts with mutations in regulatory cells and is promoted by genomic instability, inflammation, and interaction within the tumor microenvironment
Causes of carcinogenic mutations
DNA (Deoxyribonucleic acid) mutation:
**Environmental carcinogens: Non-inherited (somatic)
*Genetics: Inherited (germline): 853 Germline variants *******(BRCA1/BRCA2)
4 mutations in regulatory DNA (cell)
Proto-oncogenesis
Tumor suppressor genes
Caretaker genes
Chromosome translocation
Proto-oncogenes
Normal cellular genes are important regulators of normal cellular processes promoting growth.
***When mutated; alterations in the expression of these cells result in oncogenes enabling cancer cells to be self-sufficient in growth
_____________is a commonly mutated Proto-Oncogene; in pancreatic and colorectal cancers. Occurs at a single location of DNA; or a single base pair
Ras (A point mutation)
Tumor suppressor genes
A gene whose protein product inhibits cell division/proliferation, thereby preventing the uncontrolled cell growth that contributes to cancer.

When mutated, these genes no longer suppress proliferation.
(out of control)
__________ ____________a tumor suppressor gene is mutated in childhood retinoblastoma and many lung, breast, and bone cancers
RB gene
Caretaker Genes (DNA Repair Genes)
-repairs DNA that's damaged by environmental factors (carcinogens)
-Repair the errors in DNA that occur during replication
-In some pt's gene may not be activated, making it easier for a mutation to occur

-but if not corrected, these errors can result in mutations that activate oncogenes/inactivate tumor suppressor genes
Chromosome translocation
A piece on one chromosome is transferred to another chromosome as the cells divide
Chromosome translocation
In Burkitt lymphoma cell, the __________________________ a proto-oncogene is located on chromosome 14, which is normally located on Chromosome 8
MYC (portion of DNA)
Chromosome translocation In Chronic myeloid leukemia (CML), the __________________________ a is located on chromosome 22 and is fused to ABL gene, but is normally located on Chromosome 9. This translocation is also known as __________________________________. The fusion makes a protein call ______________________________which promotes proliferation of myeloid cells.BCR gene: Philadelphia Chromosomes: Tyrosine kinaseWhat was the original targeted tyrosine kinase inhibitor designed to target the Philadelphia Chromosome pathway?Imatinib3 Enabling factors in facilitating the development of Cancer cells and Tumor1. Genomic instability 2. Inflammation 3. Interactions between tumor cells and the surrounding normal tissue stroma or environmentGenomic instability refers to:Defective regulation resulting in an increased tendency for genome alterations and mutability during cell life cycles -The direct effects of replication and chromosomal segregation -Cancer cells are less stable than normal cellsGenomic instability Hereditary nonpolyposis colon cancer syndrome (HNPCC)Characterized by microsatellite instability (MSI) Microsatellites: a series of tandem repeated nucleotides Normal cells: have a consistent length of nucleotidesGenomic instability EpigeneticsMechanisms that may change the activity of a gene without changing the DNA sequence Ex: Adding or removing methyl groups from DNA affects gene transcription Affected by: Diet; environment; medicationsDNA methylationThe addition of methyl groups (—CH3) to bases of DNA after DNA synthesis may serve as a long-term control of gene expression. -Adding or removing methyl groups from DNA affects the transcription of genes -If DNA is not transcribed it is silenced -Caused by: Diet; environment; medicationsWhy is DNA methylation so important?Most DNA methylation is essential for normal development, and has an important role in a number of key processes: ***Genomic imprinting ***X-chromosome inactivation ***Suppression of repetitive element transcription and transposition When dysregulated, it contributes to diseases like cancer.HypermethylationInactivates transcription of DNA > Methylation makes DNA muteHypomethylation or lack of methylationActivation of oncogenes genes and the resulting formation of tumors. (over expression) < Methylation of DNA. Ex: Inhibiting a tumor suppressor gene from being transcribedA medication that treats Myelodysplastic syndrome (MDS) that hypomethylates is _______________________________.Decitabine ***Some cancers are associated with hypermethylation of regulatory areas of genesInflammation and CancerChronic inflammation produces mutagenic agents -Supplies signaling molecules to the tumor microenvironment -Reactive Oxygen species: polymorphonuclear neutrophils (PMNs) at the site of inflammation cause endothelial dysfunction and tissue injury. ~Cytokine release from inflammatory cells ~Cytokines produce free radicals -> cause mutation promotion. ~Decreased response to DNA damage (by caretaker genes)Tumor MicroenvironmentLocal conditions that enable cancer growth, brought about by interactions of tumor cells with stroma, inflammatory cells, blood vessels, etc. -Growth factor -Survival factor -Proangiogenic factors -Extracellular matrix modifying enzymes -Inductive signals that lead to activation of epithelial mesenchymal transition (EMT) and other hallmark promoting programsStromal cellsCells that contribute to the development of multiple tissues and blood cells -connective tissue -blood vessels -Immune inflammatory cells (macrophages/lymphocytes/fibroblast)How does the interaction between tumor cells and normal tissue stroma cells lead to tumor growth/metastasis?They communicate through reciprocal pathways eliciting an immune and stromal response to stimulate formation of new blood vessels (angiogenesis) EX: Metastatic colon cancer produces 5 x as much epidermal growth factor receptor (EGRF) as normal tissue the increase in epidermal growth factor receptor (EGRF) signal mediates TGF-a Transforming growth factor alpha (TGF-a) is Vascular endothelial growth factor (VEGF) it initiates normal angiogenesis in normal endothelial cells and stimulates lymph angiogenesis, producing an increase in tumor growth spread to lymph nodes.What is a monoclonal antibody that blocks ligand binding to EGFR? Used in + EGFR pts to reduce primary tumor size and lymphatic spreadCetuximabCommon sites for Metastasis Stomach Rectal Pancease Ovaries Colon (Sister Ruth Plays the Organ for Colin, PLLease)Peritoneal, Liver,LungsCommon sites for Metastasis Bladder Breast Thyroid Melenoma Uterus. (Bret Bet Teresa a Million Uros)All- Bone Liver Lungs Breast- + Brain Melanoma- + Brain Skin Muscle Uterus- +Peritoneum VaginaCommon sites of metastasis Kidney LungAll- Adrenal gland Bone Brain Liver Lung Lung + Other