Cellular and physiological roles for phospholipase D1 in cancer

Abstract

Phospholipase D enzymes have long been proposed to play multiple cell biological roles in cancer. With the generation of phospholipase D1 (PLD1)-deficient mice and the development of small molecule PLD-specific inhibitors, in vivo roles for PLD1 in cancer are now being defined, both in the tumor cells and in the tumor environment. We review here tools now used to explore in vivo roles for PLD1 in cancer and summarize recent findings regarding functions in angiogenesis and metastasis.

Keywords: Angiogenesis; Animal Model; Cell Signaling; Metastasis; Phospholipase D.

FIGURE 1.

Graphic depiction of PLD1 roles in tumor progression. Upper left, cancer cells in a primary tumor are shown piling up in place of the organized epithelial cell layer. Not shown: evidence has been published to suggest that PLD or PLD1 specifically may affect the steps leading up to this stage through 1) stimulating Ras activation to increase proliferation, 2) generating survival signals that suppress apoptosis in settings of nutrient deprivation, hypoxia, and anoikis driven by detachment from the basal lamina extracellular matrix, and 3) regulating cell polarity to enable the detachment (8–19). Shown: VEGF released by tumor cells stimulates neoangiogenic vascularization of the tumor. Middle left, PLD1 may also increase tumor cell invasive capacity via MMP release and facilitate migration and thus entry into circulation. Once in circulation, the tumor cells aggregate through interaction with platelets and fibrinogen, shielding the tumor cells from the immune system, physically protecting them from flow stress, promoting EMT, and (lower left) assisting them in seeding at distal metastatic sites. Right, in the absence of PLD1, vascular endothelial cells respond poorly to the VEGF released by the primary tumor, strongly decreasing neoangiogenesis. For those tumor cells that enter into circulation, decreased interaction with platelets leads to reduced efficiency of metastatic seeding, via any or multiple of the mechanisms listed above.