Exploring Comprehensive Gene Expression Analysis of Prostate Cancer Reveals Distinct Transcriptional Programs Associated With Metastatic Disease Through GenMAPP

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Exploring Comprehensive Gene Expression Analysis
of Prostate Cancer Reveals Distinct
Transcriptional Programs Associated With
Metastatic Disease Through GenMAPP MappFinder
LaTulippe Eva, Satagopan Jaya, Smith Alex, Scher
Howard, Scardino Peter, Reuter Victor, and
William G. Cancer Research 2002 Aug 1 62,
4499-4506.

• Kevin Paiz-Ramirez
• Janelle N. Ruiz
• Biology 398.01
• Department of Biology
• Loyola Marymount University
• April 21, 2010

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Outline

1. Previous study examined differences in gene
   expression between primary and metastatic tumors
2. Using GenMAPP and MAPPFinder to reexamine
   microarray data
3. Resultsgene ontological differences b/w
4. Metastatic versus Primary tumors
5. Hormone-treated versus Primary tumors
6. Hormone-treated versus Metastatic tumors
7. Androgen-induced versus Metastatic tumors
8. Interpretation
9. Significance of differences in biological
   processes between four groups
10. References

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Previous study explored function of unknown genes
which may identify potential therapeutic targets

• La Tullippe, et al. performed high-throughput
  gene
• expression using Affymetrix chips to study
  prostate cancer
• metastasis
• Used tissue biopsies collected from 1993-1999
  from
• 3 non-cancerous patients
• 23 primary prostate cancer patients
• 9 metastatic prostate cancer patients
• Genes were considered to be differentially
  expressed if they differed 3 fold between groups
• Highly differentially expressed genes between
  metastatic and primary tumors involved in
• Cell cycle regulation mitosis signaling DNA
  replication

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Reexamining Microarray Data Using GenMAPP and
MAPPFinder

• Purpose confirm findings of previous study and
  search for novel cellular processes involved in
  metastasis
• Method
• GenMAPP and MAPPFinder
• Group highly differentially expressed genes based
  on similarities in biological processes
• MAPPs represent biological pathways and other
  functional groupings of genes
• Genes assigned to gene ontology (GO) terms based
  on model organism database

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Preparing Data for GenMAPP

• The Log2 of the ratio of the means was calculated
  for
• Metastatic vs. primary tumors
• Hormone-treated vs. primary tumors
• Hormone-treated vs. metastatic tumors
• Androgen-independent vs. primary tumors
• Number of errors 1793/11977
• Our statistical criteria
• Z score gt 2
• P value lt0.05
• Percent Changed Raged 15-18

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Increased Processes Between Metastatic and
Primary Tumors
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Metastatic and Primary Tumors Presented Increases
in Mitosis

• Mitosis
• Relates to cell division
• Spindle Organization
• Assembly, arrangement of constituent parts, or
  disassembly of the microtubule spindle during a
  mitotic cell cycle.
• Chromosome Segregation
• The process by which chromosomes are organized
  into specific structures and then physically
  separated to two or more sets.
• DNA Replication Initiative
• Involves the separation of the DNA double helix,
  the recruitment
• of DNA polymerases and the initiation of
  polymerase action.

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Decreased Processes Between Metastatic and
Primary Tumors
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Metastatic and Primary Tumors Presented Decreases
in Muscle Function

• Muscle Contraction
• Force generated within muscle tissue involving
  chemo-mechanical energy conversion carried out by
  the actin/myosin complex activity
• Chromatin Remodeling Complex
• Any complex that mediates dynamic changes in
  eukaryotic chromatin
• Oxidoreductase Activity
• The oxidation state of an atom within a molecule
  is altered.

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Increased Processes Between Hormone Treated and
Primary Tumors
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Hormone Treated and Primary Tumors Presented
Increases in Chemotaxis

• Activation of MAPK Activity
• Activates inactive enzyme MAP kinase
• Leukocyte Chemotaxis
• Movement of Leukocytes in response to external
  stimulus
• Metanephros Development
• Development of the kidneys
• Immune Response

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Decreased Processes Between Hormone Treated and
Primary Tumors
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Hormone Treated and Primary Tumors Presented a
Decrease in Nucleosome Activity

• Nucleosome Activity
• Increase in Nucleosome activity, the primary
  packing unit of DNA
• Chromatin Activity
• Including Chromatin assembly and Chromosomal part
  
• DNA Packaging
• Any process by which DNA and associated proteins
  are formed into a compact orderly structure.

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Increased Processes Between Hormone-Treated and
Metastatic Tumors

• Muscle contraction
• Change in muscle geometry in response to hormone
  treatment
• Immune response
• Hormone-treated tumors more likely to be
  recognized by immune system
• Activity of enzymes that break down proteins
• Break down of tumor in response to hormone
  treatment
• Cell signaling
• Calcium-mediated signaling mechanoreceptor
  differentiation
• Retinoid binding and Glutathione Transferase
  activity
• Increased development of genitalia
• Genital maturation, progress through cell cycle
  to cell death or senescence

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Decreased Processes Between Hormone-Treated and
Metastatic Tumors

• Immune Regulation
• Cytokine binding, T-cell proliferation
• Conflicting less likely to be attacked by
  immune system?
• Response to radiation
• Hormone treatment and radiation in conflict?
• Cell signaling
• Light Sensitivity
• Phototransduction transferring light (photons)
  into signals
• Photodynamic therapy for prostate cancer
  (http//www.prostatepdt.com)
• Regulation of catabolism and polymetabolic
  processed
• Fidelity during transcription/translation
• DNA replication/repair RNA polymerase activity
  RNA polymerase binding

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Increased Processes Between Androgen-Independent
and Primary Tumors

• Mitosis/cell cycle
• M phase, regulation, cell cycle checkpoint,
  chromatin segregation
• Spindle structures
• Important in cell division
• Deoxyribonuclease and exonuclease activity
• Nucleic acid degradation
• Damaged DNA binding
• Indicates increased DNA damage
• Cell Signaling
• Negative regulation of transferase protein
  kinase activity
• Spliceosome assembly
• Microtubule motor activity

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Decreased Processes Between Androgen-Independent
and Primary Tumors

• Ion channels
• Extracellular ligand-gated excitatory
  extracellular ligand-gated anion binding
  chloride ion binding etc
• Cell Signaling
• NADP synapse
• Receptor Activity
• GABA GABA-A glutamate neuropeptide (binding
  transport)
• Muscle Contraction
• Change in shape AI larger
• Negative regulation of cell size/growth
• Acute Phase Response
• Monooxygenase activity

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Metastatic Tumors Demonstrate Greater Cell Cycle
Activity Than Primary Tumors

• Metastatic tumors show greater relative levels of
  genes involved in mitotic processes
• Replicate faster than primary tumors
• Confirms La Tullippe, et al. proliferation data
• Metastatic tumors show decrease in muscle
  contraction
• These tumor cells may tend to grow larger than
  primary tumors
• Metastasis tumors show decrease in chromatin
  remodeling
• Loss of chromatin remodeling may be important to
  metastasis

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Hormone Therapy May be More effective in Treating
Primary Tumors Than Metastatic Tumors

• Primary tumors treated with hormone therapy show
• Increase in immune activation
• Decrease in chromosomal activity indicating a
  possible decrease in cell replication
• Metastatic tumors treated with hormone therapy
  show
• Increase and decrease in immune response
• Increase in development of genitalia
• Increase in cell signaling
• Decrease response to radiation and light therapy
• Decrease in fidelity during transcription/translat
  ion

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Androgen-Independent Tumors are Similar in Their
Biological Processes to Metastatic Tumors

• AI tumors show greater relative levels of genes
  involved in mitotic processes
• Replicate faster than primary tumors
• AI tumors show decrease in muscle contraction
• AI may grow larger than primary tumors
• AI tumors have greater nucleic acid degradation
  processed than primary tumors
• AI tumors show decrease in cell signaling/ion
  channel activity
• AI tumors may not respond as well to hormone
  treatment as primary tumors

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References

• LaTulippe E, Satagopan J, Smith A, Scher H,
  Scardino P, Reuter V, and Gerald
  WL. Comprehensive gene expression analysis of
  prostate cancer reveals distinct transcriptional
  programs associated with metastatic
  disease. Cancer Res 2002 Aug 1 62(15) 4499-506.