|Elsasser, Theodore - Ted|
Submitted to: Journal of Molecular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/5/1996
Publication Date: N/A
Citation: Interpretive Summary: Once initiated, tumor cell growth occurs often independent of signals originating outside the tumor. There were few mechanisms that adequately explained how tumor cells proliferated in the absence of outside signals. Recently a hypothesis was confirmed that one important mechanism of tumor cell growth involved the production of necessary growth factors by the tumors themselves and that the same cells making the growth factors also contained receptors to these same growth factors. As such the cell basically stimulated itself and its neighbors to grow and proliferate. With the recognition of this process, an intensive search began to identify which growth factors are being produced by tumor cell lines. The present research identified the newly discovered vascular peptide adrenomedullin as a growth factor produced by most tumor cells and these cells also contain receptors for this peptide. This tumor cell growth factor is necessary for many normal actions of normal tissues in the body as well. What is interesting about this peptide is that not only does it stimulate tumor cell growth, but it appears to play a role in the invasion of a solid tumor into normal tissues by stimulating angiogenesis, the formation of blood vessels, so that the tumor can always have its command of nutrient supply. In a way, adrenomedullin assists cells in partitioning nutrients to the tumor cell. It may be possible to use adrenomedullin as an early marker of cancer and possible slow down tumor growth by blocking adrenomedullin production by tumors.
Technical Abstract: Although adrenomedullin (AM) previously has been identified in human tumors, its role has remained elusive. Analysis by RT- PCR revealed AM mRNA in 18 of 20 human normal tissues representing major organs, and 55 out of 58 (95%) malignant cell lines. Western blot and HPLC analysis showed immunoreactive AM species of 18, 14 and 6 kDa that are consistent with the precursor, intermediate product and active peptide, respectively. Immunohistochemistry and in situ RT- PCR performed on paraffin- embedded tumor cell lines of various tissue origins exhibited AM cytoplasmic staining. Neutralizing monoclonal AB to AM inhibited tumor cell growth in a dose-dependent manner, an effect that was reversed with the addition of exogenous AM. Responding tumor cells were shown to have approximately 50,000 AM receptors/cell by Scatchard analysis with 125-I-AM and expressed AM receptor mRNA by RT- PCR . Our data showed that 27 of the 36 tumor cell lines expressed AM receptor and all expressed the AM ligand. In the presence of AM, cAMP levels were shown to increase in tumor cell lines. Our collective data demonstrate that AM and AM receptor are expressed in numerous human cancer cell lines of diverse origin and constitute a potential autocrine growth mechanism that could drive neoplastic proliferation.