Download Exploring Comprehensive Gene Expression

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
Outline
I.
Previous study examined differences in gene
expression between primary and metastatic tumors
Using GenMAPP and MAPPFinder to reexamine
microarray data
Results—gene ontological differences b/w:
II.
III.
I.
II.
III.
IV.
IV.
Interpretation
I.
V.
Metastatic versus Primary tumors
Hormone-treated versus Primary tumors
Hormone-treated versus Metastatic tumors
Androgen-induced versus Metastatic tumors
Significance of differences in biological processes between
four groups
References
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
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
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 > 2
– P value <0.05
– Percent Changed Raged 15-18
Increased Processes Between Metastatic
and Primary Tumors
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.
Decreased Processes Between
Metastatic and Primary Tumors
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.
Increased Processes Between Hormone
Treated and Primary Tumors
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
Decreased Processes Between Hormone
Treated and Primary Tumors
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.
Increased Processes Between HormoneTreated 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
Decreased Processes Between HormoneTreated 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
Increased Processes Between AndrogenIndependent 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
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
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
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/translation
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
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.