title: 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.affiliation: Laboratory of General Physiology, Department of Biology and Biotechnology "Lazzaro Spallanzani", via Forlanini 6, 27100 Pavia, Italy. Electronic address: francesco.moccia@unipv.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Moccia
authors.affiliation: Unit of Clinical Epidemiology and Center for the Study of Myelofibrosis, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo Foundation, Piazzale Golgi 19, 27100 Pavia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Poletto
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D015220:Calcium Channels; D009363:Neoplasm Proteins; D002118:Calcium
keywords: Endothelial progenitor cel; Orai1; Stim1; TRPC1; Tumor vascularization; Vascular endothelial growth facto