Purinergic mechanisms in breast cancer support intravasation, extravasation and angiogenesis

Abstract

Several advances have recently expanded models of tumor growth and promoted the concept of tumor homeostasis, the hypothesis that primary tumors exert an anti-proliferative effect on both themselves and subclinical secondary metastases. Recent trials indicate that the characterization of tumor growth as uncontrolled is inconsistent with animal models, clinical models, and epidemiological models. There is a growing body of evidence which lends support to an updated concept of tumor growth: tumor homeostasis. In the case of breast cancer, if not all metastasizing tumors, these advances suggest an inconvenient truth. That is, if breast tumor cells metastasize to distant sites early in the tumorigenesis process, then removal of a breast tumor may hasten the development of its metastases. We explore the heretofore unappreciated notion that nucleotides generated by tumor cells following the secretion of an ADP-kinase can promote metastasis and support angiogenesis. Evidence is presented that blockade of the actions of nucleotides in the setting of newly diagnosed breast cancer may provide a useful adjunct to current anti-angiogenesis treatment.

Figure 1. Purinergic Mechanisms Supporting Breast Tumor Metastasis

The role of purines is described in the context of the events associated with metastasis. Evidence is described in the text.

Fgure 2. Secreted NDPK Mediates P2YR/VEGFR-2 Activation in Tumor Angiogenesis

We propose that breast cancer-secreted sNDPK-B is a significant angiogenesis promoter. sNDPK-B is secreted as a phosphoprotein [48] and elevates ATP levels in both arterioles and capillaries by re-phosphorylating ADP. Continued rounds of ATP production (enhanced normally from endothelium by sheer and agonists such as bradykinin (BK), are generated by sNDPK-B at the expense of nucleotides such as GTP released from necrotic cells in the metastatic environment. Extracellular ATP and ADP activates P2Y₁ receptors on vascular ECs, which transactivates VEGFR2 to induce angiogenesis [55]. Additional events consistent with metastasis are supported by sNDPK-B; ATP inhibits platelet aggregation [167] maintaining blood flow despite the presence of foreign tumor cells; activation of P2Y receptors by ATP and ADP results in the release of nitric oxide (NO) and prostacyclin (PGI₂) from endothelial cells leading to vasodilatation in arterioles. Breakdown of ADP to adenosine (ADO) inhibits platelet aggregation [168] and dilates venules [169] consistent with increasing the dissemination of tumor cells to distant sites. Dynamic regulation of ATP/ADP levels by sNDPK-B activates VEGFR2 even in the absence of VEGF [55]. At distant sites, P2Y receptor activation may be utilized by the metastatic cells to initiate angiogenesis early in metastasis when VEGF levels are low or absent [170] and will sum with VEGF levels to maximize angiogenic potential [55]. Thus we propose that dual inhibition of P2Y₁R and VEGFR2 signaling may provide an effective mode of combination anti-angiogenic adjuvant therapy. P2Y₁R-VEGFR2 signaling may be important in describing and understanding the VEGF signaling required for endothelial homeostasis in both tumor as well as normal vasculature.