Adrenomedullin is a cross-talk molecule that regulates tumor and mast cell function during human carcinogenesis

Enrique Zudaire, Alfredo Martinez, Mercedes Garayoa, Rúben Pío, Gurmeet Kaur, Michael R. Woolhiser, Dean D. Metcalfe, William A. Hook, Reuben P. Siraganian, Theresa A. Guise, John M. Chirgwin, Frank Cuttitta

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Abstract

We have previously demonstrated that adrenomedulin (AM) plays a critical role as an autocrine/paracrine tumor cell survival factor. We now present evidence thai AM is an important regulator of mast cell (MC) function and that this modulation is potentially involved in tumor promotion. AM induced histamine or β-faexosaminidase release from rat and human MCs through a receptor-independent pathway. AM was chemotactic for human MCs and stimulated mRNA expression of vascular endothelial growth factor, monocyte chemoattractant protein-1, and basic fibroblast growth factor in this cell type. Differentiated but not undifferentiated human MCs responded to hypoxic insult with elevated. AM mRNA/protein expression. Using confocal microscopy, we identified AM-producing MCs in tumor infiltrates of hmnan breast and lung cancer patients. In mixed culture assays the AM-producing human MC line HMC-1 augmented both anchorage-dependent and -independent growth of human lung cancer A549 cells, an effect that was suppressed by MC-targeted siRNA AM knockdown. Finally, HMC-1 cells induced in vivo angiogenesis as assessed by directed in vivo angiogenesis assay analysis; neutralizing anti-AM monoclonal antibody blocked this ability. Our collective data suggest a new role for AM as a cross-talk molecule that integrates tumor and MC communication, underlying a unique promotion mechanism of human cancers.

Original languageEnglish (US)
Pages (from-to)280-291
Number of pages12
JournalAmerican Journal of Pathology
Volume168
Issue number1
DOIs
StatePublished - Jan 2006

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Zudaire, E., Martinez, A., Garayoa, M., Pío, R., Kaur, G., Woolhiser, M. R., Metcalfe, D. D., Hook, W. A., Siraganian, R. P., Guise, T. A., Chirgwin, J. M., & Cuttitta, F. (2006). Adrenomedullin is a cross-talk molecule that regulates tumor and mast cell function during human carcinogenesis. American Journal of Pathology, 168(1), 280-291. https://doi.org/10.2353/ajpath.2006.050291