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Lecture

Tumorigenesis.docx

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Department
Biology
Course Code
BIOLOGY 2B03
Professor
Richard B Day

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April 2 , 2013 Biology 2B03: Cell Biology Tumorigenesis Cancer Biology - tumorigenesis can stem form errors in signalling pathways and cell cycle regulation mechanisms that we have discussed Objectives - identify the characteristics of cancel cells - describe the hallmarks/acquired capabilities of cancer cells - describe the multi-hit model of tumor development - identify the categories of genetic targets - differentiate between tumor suppressors and oncogenes Stages of Tumor Development - benign tumor:  slow growth, localized  closely resemble normal cells  express normal cell-specific markers  can become malignant as they have gained more of the activities typical of cancerous cells - malignant tumor:  divide rapidly  high nucleus/cytoplasm ratio  less differentiated than normal cells  loss of cell-specific markers  invade surrounding tissue - pap smear to detect cervical cancer Human Liver Tumor - high nucleus/cytoplasm ratio in dark staining tumor cells - tumor cells:  less differentiated  characteristics of rapidly growing cells including high nucleus to cytoplasm ratio  prominent nucleoli  few specialized structures (undifferentiated) Metastasis - spread of tumor cells, enter circulatory system - proliferate and establishment of 2 area of tumour growth - loss of cell-specific markers - once they enter into the circulatory system they can go any where in the body, some of these cells can rest and stop in a second area - secondary tumor is usually fatal - same initial tumor that has moved - metasized melanosarcoma invading the liver - can see melanin in cells that are now in the liver - accumulating many mutations and not undergoing regulated cell death The Hallmarks of Cancer - which genes are disrupted, resulting in each of these acquired characteristics? - But one or two processes alone may be affected April 4 , 2013 Genetic Basis for Cancer - Change in the genetic level attributed to cancer - Mutations that occur during adult lives - Result of cells native to our body: our own cells changing in some way - Normally grow in a monolayer: all cells are toughing, the contact is inhibitory and prevents further division - Transformation by adding a piece of the genome that came from human cancerous cells – narrowing down to the pieces capable of giving these changes in behaviour - Foci of cells divide more rapidly, pilling on top of each other - Genetic markers are gone - Added extra DNA but we haven’t added new cells - Cells are aneuploidy, not undergoing cell death, can divide indefinitely, can undergo cell division without having growth factors st - 1 evidence that genetic material can cause tumorigenesis: DNA from cancer cells transform cultured cells: oncogenic transformation – taking a normal cell and transforming it into a cancer cell - transformed cells :similar to tumor cells - altered morphology, reduced need for growth factors, altered chromosome complement (aneuploidy), avoid apoptosis - transformed cells are rounded and less adherent - do not enter G 0 Oncogenes - any gene that encodes a protein capable of transforming cells in culture or inducing tumors in animal - normal cellular gene called a proto-oncogene - can also induce tumours in animal models - e.g.:  proto-oncogene = ras the normal cellular gene  oncogene = ras , codes for constitutively active Ras protein - but, is one oncogene enough: we need more than one gene to contribute to the formation of tumours Two Broad Classes - proto-oncogenes: mutants (oncogenes) = increased activity - tumor suppresors: mutants = loss of restraint, components involved in checkpoints - loss of cell regulation that gives rise to cancer is due to genetic damage in somatic cells, but increases susceptibility linked to inherited mutations. - More susceptible to cancer if you have inherited genetic damage related to cancer Multi-Hit Model - evidence indicates that tumorigenesis is a multistep process that reflect genetic changes - evidence: 1) analysis of tumours - a tumour is derived from a single cell (clonal colony of a single cell) - analysis of DNA from cells within a human tumour shows that tumour cells share the same genetic mutations (somatic mutations) - mutations in multiple genes are needed to convert a normal cell to a malignant cell - note: somatic mutations: mutations in the DNA body cell (cells that are not part of the germline) share common somatic mutations. Share characteristics such as X-inactivation Human Colorectal Cancer - categorized based on the morphology of the tumour - first step – loss of function of APC (tumour suppressor) benign polyps. See increased cell proliferation. - Second step – cells then get some or all of the other mutations in varying order, Ras , DCC, p53. See uncontrolled cell proliferation - Third step, fourth step – mutations in tumour suppressors and/or oncogenes. Leads to malignant carcinoma and metastasis. - Cells skipping checkpoints making it more likely for other mutatiosn to accumulate - Process is slow at first then speeds up Multi-Hit Model - Line trends up toward the right hand side, consistent with multi-hit model - Different rates at which these cancers occur, some cells have a tendency to accumulate mutations over time - evidence 2) epidemiological studies - cancer incidence increases exponentially with age, mutations, accumulate in multiple genes over time - single mutation gives aberrant cell growth advantage over normal cells, 2 nd mutation add another tumor ability (angiogenesis for eg), 3 mutation allows cell and its progeny to escape into blood, seen in cooperativity of oncogenes - evidence: 3) mouse model - adding DNA to induce tumours - cooperativity of oncogenes: progression is more rapid when mutations are both expressed - Myc or Ras activation alone: tumours occur in mice at low rate - High rate of tumourigenesis seen with more than one oncogene - Long latency of tumour formation also reflects need to acquire multiple mutations (not just in ras and myc) - As mice get older they have a higher rate of tumour indicating that mutations appear as we age Parallel Pathways of Tumorigenesis - aware of specific defects in individual patients in order to properly treat the patient The Genetic Basis of Cancer - proto-oncogenes and tumour suppressors (checkpoint controls, DNA repair) - general: cancer cells acquire autonomy from external regulatory signals: lower requirement for growth-stimulatory signals and diminished sensitivity to inhibitor signals. Gain-of-Function Mutations in Proto-Oncogenes - most proto-oncogenes are essential and conserved - required for activating cell division - activation of proto-oncogene to oncogene involves gain-of-function mutation - classes of proto-oncogenes:  growth factors  hormone receptors (pathways that induce cell division)  signalling proteins e.g. Ras  transcription factors e.g. Fos, Myc  anti-apoptosis proteins (keep cells alive) Loss-of-Function Mutations in Tumour Suppressors - tumour suppressors usually inhibit cell proliferation (brakes of the cell), so loss of function = cancer - both alleles must be inactivated or lost to promote tumour development - classes of tumour suppressors:  hormone receptors (pathway that inhibit cell division)  pro-apoptosis proteins (remove damaged cells)  cell cy
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