Background: Invasive tumor growth and metastasis require the formation of a chaotic
network of blood vessels that nourish cancer cells and provide them with a direct access to
peripheral circulation, which is essential for them to diffuse throughout the organism. Tumor
vascularization is sustained by multiple mechanisms, including sprouting angiogenesis and
vasculogenesis, which consists in the recruitment of endothelial progenitor cells (EPCs) from either
the bone marrow or the arterial wall. Tumor endothelium presents significant morphologic, genetic
and functional differences as compared to normal cells.
Methods: Recent work has shown that the Ca2+ signaling machinery is heavily remodeled in both
tumor endothelial cells (TECs) and tumor-associated EPCs (T-EPCs). The rearrangement of the Ca2+
toolkit in TECs and T-EPCs leads to a dramatic improvement of their pro-angiogenic activity and
increases cancer resistance to chemotherapeutics and anti-angiogenic treatments. Herein, the major
changes involved in this process are analyzed.
Results: The major changes observed include the reduction in the endogenous Ca2+ reservoir, the upregulation
of store-operated Ca2+ entry or TRPC5 and the alteration in TRPV4 levels. Additionally, a
growing number of studies revealed that other transporters involved in Ca2+ homeostasis are
aberrantly expressed in TECs, including Na+/H+ exchanger, chloride intracellular channels, and
nicotinic acetylcholine receptors. This emerging field of investigation is, therefore, coming of age
because of its tremendous therapeutic potential.
Conclusions: Understanding the impact of Ca2+ dysregulation in tumor vascularization is mandatory
to circumvent patient refractoriness to current anti-cancer regimens.