cancer 1

• Cancer

  a group of disorders as a result of accumulation of somatic mutations; Genetic disease
• Characteristics or Hallmarks of cancer cells

  uncontrolled cell division

  self suffient growth growth

  Defective DNA repair

  immortal

  capacity to invade surrounding tissue

  induce angiogenesis
• Cancer


  Multistep process requiring multiple mutations

  results from mutated gene products or abnormally expressed genes
• Multistep Process That Requires Multiple Mutations

  normal colon epithelium --at 30-50 years APC cause small adenoma--at 40-60 kras cause large adenoma at 50-70 carcinoma developmented
• Clonal origin

  all cancer cells in primary and secondary tumors are clonal
• clonal

  originated from a common ancestral cell that accumulated numerous specific mutations
• Reciprocal translocations and X-inactivation

  demonstrate that cancer cells are clona
• Reciprocal chromosomal translocations


  : Chronic myeloid leukemia: Reciprocal translocation between chromosome 9 and 22 • Translocation is present in all tumor cells

  
• X-chromosome inactivation

  All cancer cells within a tumor, both primary and metastatic, within one female individual contain the same inactivated X chromosome
• hierarchial cancer stem cell model

  Tumor cells give rise to cancer stem cells that have capacity for self-renewal
• Cancer can result from

  increased cell division

  decreased rates of cell death
• • Cells that stop proliferating enter G0

  Do not grow or divide but are metabolically active (neurons)
• G1/s checkpoint

  cell monitors size and DNA intergrity
• G2/M checkpoint

  cell monitor DNA synthesis and damage
• M checkpoint

  cell monitors spindle formation and attachment to knetochores
• Cell-cycle is regulated by cyclins and cyclin-dependent kinases (CDKs)

  • Levels of cyclin D2 increase at the end of G1 G1/S checkpoint

  Levels of cyclin B increase at the end of G2 phase G2/M checkpoint
• Cyclin B with CDK

  causes phosphorylation of M phase proteins

  • Overexpression of cyclins or cyclin dependent kinases (CDKs) may result in excessive cell division. can cause cancer
• • Signal transduction for cell division

  Signal transduction initiates gene expression that propels cell out of G0 and back into cell cycle (Cell is stimulated to divide)

  stimulated by external growth factors
• Protooncogenes

  code for proteins that have defects in signal transduction pathways involving growth factors.
• Proto-oncogenes

  Genes whose products promote cell growth and division

  • Transcription factors that stimulate expression of other genes • Signal transduction molecules that stimulate cell division • Cell-cycle regulators that move cell through cell cycle
• Tumor suppressor genes

  • Regulate cell-cycle checkpoints and/or initiate process of apoptosis

  Mutations in tumor suppressor genes result in uncontrolled cell division
• DNA repair genes

  • Genes code for proteins involved in DNA repair • Mutations in DNA repair genes increases the risk of cancer
• Oncogene

  • Mutated proto-oncogene is converted to an oncogene

  gain of function alteration

  dominant phenotype

  on 1 allele need to be mutated to cause cancer
• Mutated tumor-suppressor genes

  can cause cancer

  loss of function mutation

  • Both copies must be lost to result in cancer (reccesive)
• Growth factor signal transduction cascade

  Growth factor binds to receptor

  activates ras

  ras activitates downstream proteins

  activates nuclear transcription factor
• oncogene myc

  gene codes for a transcription factor in the growth factor signaling pathway

  overproduction increase transcription of gene and activate cell division
• Ras Proto-Oncogene

  GTP binding cytosolic protein

  then triggers downstream signals for cell division

  hydrolysis of GTP inactivated ras
• Overexpression of ras

  constant activation of cell cycle
• Mutant ras

  s constantly active (point mutations); Generally, mutant ras loses its GTPase activity and is constitutively active
• Abl

  protooncogene gene activated in chronic myeloid leukima

  Abl gene on chromosome 9

  Bcr on chromosome 22

  abl moves next to bcr (translocation)

  bcr-abl fusion protein
• bcr abl fusion protein

  always active

  causes uncontrolled division leading to cancer
• Gleevec

  inhibits tyrosine kinases

  inhibits bcr-abl fusion protein
• double minute

  extrachromosomal fragment s of oncogen
• homegeneous staining region

  multiple copies of oncogene on a chromosome