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A Serial Analysis of Gene Expression (SAGE) database analysis of chemosensitivity: comparing solid tumors with cell
Wilfred D Stein1, Thomas Litman, Tito Fojo
1Department of Biological Chemistry, Silberman Institute of Life Sciences' Hebrew University, Jerusalem, Israel.
Abstract:
Drug sensitivity and resistance has been most extensively studied in cell lines carried in tissue culture. Furthermore, cell lines have been widely used in testing new anticancer agents, despite the widely recognized observation that cell lines are more sensitive to cytotoxic drugs than are their corresponding solid tumors. We used the Serial Analysis of Gene Expression (SAGE) database to identify differences between solid tumors and cell lines, hoping to detect genes that could potentially explain differences in drug sensitivity. SAGE libraries were available for both solid tumors and cell lines from breast, colon, ovarian, pancreatic, and prostate carcinomas and from gliomas and medulloblastomas. Sixty-two genes were identified as overexpressed in tumors. The immune response and complement pathways were the significant common themes, with extracellular matrix (ECM) proteins third. For the 61 genes overexpressed in cell lines, protein synthesis was the dominant theme. We next used the SAGE database to identify genetic differences between tumor types that convey a broad range of survival to the patients that bear them as distant metastases. SAGE gene expression data were correlated with 5-year survivals documented in the SEER (Surveillance, Epidemiology and End-Results) database for patients diagnosed with "distant" or metastatic cancers. These are unlikely to be amenable to surgical resection; therefore, survival here reflects, to some extent, sensitivity to systemic therapy, i.e., chemotherapy. Using survival data as a surrogate of chemotherapy sensitivity, a spectrum can be generated, with testicular cancer at one end and pancreatic cancer at the other. Favorable 5-year survival, despite a distant presentation, correlates with expression of protein synthesis genes. Poor 5-year survival correlates with expression of cell adhesion, cytoskeletal, and ECM genes, a pattern similar to that found to distinguish solid tumors from the more cytotoxin-sensitive cancer cell lines. One interpretation is that resistance to chemotherapy may arise, in part, from the adherent, relatively inert condition (i.e., low in protein synthesis potential) of refractory cancers. Thus, attachment or ECM genes could be targets for anticancer therapy.
Insights
Cancer cell lines show higher drug sensitivity than solid tumors. Gene expression differences, particularly in immune response and extracellular matrix (ECM) genes, may explain this, offering potential new therapeutic targets.
Area of Science:
- Genomics and Molecular Biology
- Cancer Research
- Pharmacogenomics
Background:
- Drug sensitivity and resistance are critical in cancer treatment, extensively studied using cell lines.
- Cancer cell lines often exhibit higher sensitivity to cytotoxic drugs compared to their corresponding solid tumors.
- Understanding these differences is crucial for developing effective anticancer therapies.
Purpose of the Study:
- To identify gene expression differences between solid tumors and cell lines using the Serial Analysis of Gene Expression (SAGE) database.
- To explore genetic variations linked to patient survival and chemotherapy sensitivity in metastatic cancers.
- To uncover potential therapeutic targets for overcoming drug resistance.
Main Methods:
- Utilized the SAGE database to compare gene expression profiles of various solid tumors (breast, colon, ovarian, pancreatic, prostate carcinomas, gliomas, medulloblastomas) and their corresponding cell lines.
- Identified genes overexpressed in tumors versus cell lines and vice versa.
- Correlated SAGE gene expression data with 5-year survival rates from the SEER database for metastatic cancers to infer chemotherapy sensitivity.
Main Results:
- Sixty-two genes were overexpressed in tumors, predominantly involved in immune response, complement pathways, and extracellular matrix (ECM) proteins.
- Sixty-one genes were overexpressed in cell lines, with protein synthesis being the dominant theme.
- Favorable 5-year survival in metastatic cancer correlated with protein synthesis gene expression, while poor survival correlated with cell adhesion, cytoskeletal, and ECM gene expression.
Conclusions:
- Gene expression patterns, particularly those related to immune response and ECM, distinguish solid tumors from more drug-sensitive cell lines.
- Chemotherapy resistance in refractory cancers may stem from their adherent nature and reduced protein synthesis potential.
- Extracellular matrix (ECM) and cell adhesion genes represent potential therapeutic targets for enhancing anticancer drug efficacy.
