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Transforming Growth Factor (TGF) Beta Receptor 2 and Gastric Cancer

Transforming Growth Factor (TGF) Beta Receptor 2 and Gastric Cancer. Valerie h. chen. TGF Beta Pathway: TGF Beta Receptor 2 is a Ser/Thr Receptor Kinase. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.2875. Function of TGF Beta Pathway in Normal Cells.

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Transforming Growth Factor (TGF) Beta Receptor 2 and Gastric Cancer

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  1. Transforming Growth Factor (TGF) Beta Receptor 2 and Gastric Cancer Valerie h. chen

  2. TGF Beta Pathway: TGF Beta Receptor 2 is a Ser/Thr Receptor Kinase http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.2875

  3. Function of TGF Beta Pathway in Normal Cells • Pattern formation during embryonic development • Cell growth and proliferation • Cellular differentiation • Extracellular matrix production • Angiogenesis • Tissue repair • Immune regulation • Apoptosis

  4. Example: Cell Growth Inhibition via TGF Beta Pathway p21 p27, p57 Runx3 c-myc cdc25 http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.2875

  5. Gastric Background In 2008, there were ~21,500 new cases of gastric cancer and ~10,880 deaths http://i.ehow.com/images/GlobalPhoto/Articles/4586983/77857_Full.jpg Most (85%) cases of gastric cancer are adenocarcinomas that occur in the lining of the stomach (mucosa) http://www.auburn.edu/~bantawm/Notes/Digestion%20Notes_files/image010.jpg

  6. Unregulated DNA Synthesis in Gastric Cancer Park et al., Proc Natl Acad Sci 1994 .

  7. Abnormal TGF Beta Receptor 2 mRNA Transcripts and Protein Expression in Gastric Cancer FIG. 4. TGF-beta type II receptor expression. Immunoprecipitation followed by immunoblot analysis of the whole cell lysates with anti-human TGF-beta type II receptor rabbit antibody shows that expression of the type II receptor corresponds with the expression of type II receptor mRNA. Note that expression of the type II receptor was not detectable in SNU-1 and -5 (lanes 1 and 2) and was overexpressed in SNU-719 (lane 4) compared to that of SNU-16 (lane 3). FIG. 2. Northern blot analysis of TGF-beta receptor mRNA expression. Two micrograms of poly(A)+ RNA from cells treated with porcine TGF-beta 1 at 5 ng/ml (+) or a saline vehicle (-) for 48 hr were analyzed for the effect of TGF-beta on the expression of TGF-beta receptors. Hybridization with TGF-beta type II receptor cDNA shows various aberrant expression patterns of type II receptor mRNA. Type II receptor mRNA is absent or undetectable in SNU-1, -484, and -638, is increased in SNU-601 and -719, and is truncated (~1 kb) (thin arrow) in SNU-5 and -668 (in longer exposure). SNU-16, sensitive to growth inhibition by TGF-beta, expresses a full-size (~5.5 kb) type II receptor mRNA (thick arrow). Hybridization with rat glyceraldehyde phosphate dehydrogenase cDNA is show as control for mRNA loading. Park et al., Proc Natl Acad Sci 1994 .

  8. TGF Beta Receptor 2 Undergoes Genetic Alterations in Gastric Cancer FIG. 4. TGF-beta type II receptor expression. Immunoprecipitation followed by immunoblot analysis of the whole cell lysates with anti-human TGF-beta type II receptor rabbit antibody shows that expression of the type II receptor corresponds with the expression of type II receptor mRNA. Note that expression of the type II receptor was not detectable in SNU-1 and -5 (lanes 1 and 2) and was overexpressed in SNU-719 (lane 4) compared to that of SNU-16 (lane 3). Park et al., Proc Natl Acad Sci 1994 .

  9. Move from Correlation to Causation… But, that’s all correlative data… You’re right. Let’s look at cause-and-effect…

  10. Transfection of Wild Type TGF Beta Receptor 2 Restores Expression Fig. 1. Expression of TGF-beta RII mRNA in SNU-638 cells infected with MFG-TGF-beta RII. A Northern blot analysis of TGF-beta RII mRNA in the MFG-TGF-beta RII and MFG-CAT-SNU-638 cell lines. Total RNA was isolated from the MFG-TGF-beta RII and MFG-CAT-SNU-638 human gastric cancer cell lines and analyzed by Northern analysis using 32P labeled TGF-beta RII and neomycin probes. A radiolabeled probe for 5SRNA was used to control for loading. Chang et al., Cancer Research 1997.

  11. Transfection of Wild Type TGF Beta Receptor 2 Restores TGF Beta Sensitivity Fig. 2. TGF-beta I sensitivity in wild-type TGF-beta RII-expressing SNU-638 cells. A. wild-type TGF-beta RII-expressing SNU-638 cells and CAT-expressing SNU-638 cells were treated with increasing doses of TGF-beta l (0-5 ng/ml), and [3H]thymidine incorporation was examined. B. changes in cell number in DMEM + 10% fetal bovine serum were examined as a function of time with 10 ng/ml TGF-beta 1 in SNU-638-CAT cells or SNU-638-RII cells. Chang et al., Cancer Research 1997.

  12. Transfection of Wild Type TGF Beta Receptor 2 Reduces Tumorigenicity Fig. 3. Tumorigenicity of MFG-TGF-beta RII and MFG-CAT SNU-638 cells. Five X 106 cells each were injected s.c. into nude mice (n = 10). Tumor volume was followed for 5 weeks. In mice that were inoculated with TGF-beta RII-expressing SNU-638 cells, the tumor growth rate was reduced dramatically. Values are the means means±SE of established tumors. Chang et al., Cancer Research 1997.

  13. Questions?

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