May the remodeling of the Ca²⁺ toolkit in endothelial progenitor cells derived from cancer patients suggest alternative targets for anti-angiogenic treatment?

Abstract

Endothelial progenitor cells (EPCs) may be recruited from bone marrow to sustain the metastatic switch in a number of solid cancers, including breast cancer (BC) and renal cellular carcinoma (RCC). Preventing EPC mobilization causes tumor shrinkage. Novel anti-angiogenic treatments have been introduced in therapy to inhibit VEGFR-2 signaling; unfortunately, these drugs blocked tumor angiogenesis in pre-clinical murine models, but resulted far less effective in human patients. Understanding the molecular mechanisms driving EPC proliferation and tubulogenesis in cancer patients could outline novel targets for alternative anti-angiogenic treatments. Store-operated Ca²⁺ entry (SOCE) regulates the growth of human EPCs, and it is mediated by the interaction between the endoplasmic reticulum Ca²⁺-sensor, Stim1, and the plasmalemmal Ca²⁺ channels, Orai1 and TRPC1. EPCs do not belong to the neoplastic clone: thus, unlike tumor endothelium and neoplastic cells, they should not remodel their Ca²⁺ toolkit in response to tumor microenvironment. However, our recent work demonstrated that EPCs isolated from naïve RCC patients (RCC-EPCs) undergo a dramatic remodeling of their Ca²⁺ toolkit by displaying a remarkable drop in the endoplasmic reticulum Ca²⁺ content, by down-regulating the expression of inositol-1,4,5-receptors (InsP3Rs), and by up-regulating Stim1, Orai1 and TRPC1. Moreover, EPCs are dramatically less sensitive to VEGF stimulation both in terms of Ca²⁺ signaling and of gene expression when isolated from tumor patients. Conversely, the pharmacological abolition of SOCE suppresses proliferation in these cells. These results question the suitability of VEGFR-2 as a therapeutically relevant target for anti-angiogenic treatments and hint at Orai1 and TRPC1 as more promising alternatives. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

• Authors: Francesco Moccia, Valentina Poletto
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1853 Issue 9 Pg. 1958-73 (Sep 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25447551 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Calcium Channels
• Neoplasm Proteins
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Channels (metabolism)
• Calcium Signaling
• Endothelial Cells (metabolism, pathology)
• Humans
• Neoplasm Proteins (metabolism)
• Neoplasms (blood supply, metabolism, pathology, therapy)
• Neovascularization, Pathologic (metabolism, pathology, therapy)
• Stem Cells (metabolism, pathology)