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Receptor tyrosine kinases expressed in metastatic colon cancer
R J Craven1, L H Xu, T M Weiner
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine 27599.
Abstract:
Using a PCR-based cloning technique, we have isolated a series of DNA fragments coding for tyrosine kinases that are expressed in a metastatic human colon tumor, and have subsequently analyzed their expression pattern at the protein level in human tumors. We identified both the alpha and the beta forms of the platelet-derived growth factor receptor (PDGFR), axl and 8 other genes, including 3 cytoplasmic tyrosine kinases. To study their expression in human colon cancer, we performed Western blots of matched sets of normal tissues and of carcinomas from the same patient. These revealed that the alpha-PDGFR migrates predominantly as a 200-kDa band in 8/8 normal tissues, and as a 170-kDa band in 17/17 malignant tissues, as well as in colonic polyps, suggesting that expression of an isoform of this receptor may be a marker for the progression of colon cancer. Additional studies showed that the Axl receptor tyrosine kinase was expressed at 10-fold higher levels in a peritoneal metastatic nodule than in other normal and malignant tissues. Immunohistochemistry revealed Axl over-expression specifically in the malignant cells of the tumor. This indicates that over-expression and possibly a differential processing event of tyrosine kinase receptors may be involved in colon cancer, and that they are potential markers for the progression of this disease.
Insights
Altered tyrosine kinase receptor expression, including alpha-platelet-derived growth factor receptor (alpha-PDGFR) isoforms and Axl, may indicate colon cancer progression. These receptors show distinct expression patterns in normal versus malignant tissues, suggesting their potential as biomarkers.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Tyrosine kinases play critical roles in cellular signaling pathways.
- Aberrant expression of tyrosine kinases is implicated in various cancers, including colon cancer.
- Understanding specific tyrosine kinase alterations in colon tumors can reveal disease mechanisms and potential therapeutic targets.
Purpose of the Study:
- To identify tyrosine kinases expressed in metastatic human colon tumors.
- To analyze the protein expression patterns of identified tyrosine kinases in normal and cancerous colon tissues.
- To investigate the potential of these tyrosine kinases as biomarkers for colon cancer progression.
Main Methods:
- Polymerase chain reaction (PCR)-based cloning to isolate tyrosine kinase genes.
- Western blotting to analyze protein expression levels and isoforms in matched normal and tumor tissues.
- Immunohistochemistry to localize specific protein expression within tumor tissues.
Main Results:
- Identified alpha and beta forms of platelet-derived growth factor receptor (PDGFR), Axl, and other tyrosine kinases.
- Observed a shift in alpha-PDGFR migration from 200-kDa in normal tissues to 170-kDa in malignant tissues and polyps.
- Found a 10-fold increase in Axl receptor tyrosine kinase expression in metastatic nodules, with specific over-expression in malignant cells.
Conclusions:
- Altered expression and potential differential processing of tyrosine kinase receptors, such as alpha-PDGFR and Axl, are involved in colon cancer.
- These receptor tyrosine kinases represent potential biomarkers for the progression of colon cancer.
- Further research into these molecular alterations could lead to novel diagnostic and therapeutic strategies.