Effects of lysophospholipids on tumor microenvironment

Abstract

The effects of lysophospholipids (LPLs) on cancer microenvironment is a vast and growing field. These lipids are secreted physiologically by various cell types. They play highly important roles in the development, activation and regulation of the immune system. They are also secreted by cancerous cells and there is a strong association between LPLs and cancer. It is clear that these lipids and in particular sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) play major roles in regulating the growth of tumor cells, and in manipulating the immune system. These activities can be divided into two parts; the first involves the ability of S1P and LPA to either directly or through some of the enzymes that generate them such as sphingosine kinases or phospholipases, induce the motility and invasiveness of tumor cells. The second mechanism involves the recently discovered effects of these lipids on the anti-tumor effector natural killer (NK) cells. Whereas S1P and LPA induce the recruitment of these effector cells, they also inhibit their cytolysis of tumor cells. This may support the environment of cancer and the ability of cancer cells to grow, spread and metastasize. Consequently, LPLs or their receptors may be attractive targets for developing drugs in the treatment of cancer where LPLs or their receptors are up-regulated.

Fig. 1

a Sphingosine 1-phosphate (S1P) is pleotropic lysophospholipid that exerts multiple activities on cancer cells as well as normal cells. Most of these activities are inhibited by the drug FTY720 which binds S1P_1,3,4,5. b Similar to S1P, lysophospholipid (LPA) exerts different functions on normal and cancer cells

Fig. 2

Generation of the lipids described in this article. These can be classified into lysosphingolipids (e.g. S1P) and lysoglycerolipids (e.g. LPA). The enzymes that catalyze each step in theirgenerations are shown in italics

Fig. 3

High concentrations of S1P inhibit the chemotactic response of cancer as well as untransformed cells, whereas low concentrations activate this process by binding S1P₁ which activates Rac. In contrast, S1P binding to S1P₂ inhibits Rac abut stimulates Rho, resulting in inhibiting melanoma cell chemotaxis

Fig. 4

Tumor cell editing of NK cells. In step 1, cancer cells such as ovarian cancer cells secrete lysophospholipids (S1P and LPA, among others) which recruit NK cells. At the same time, these LPLs inhibit NK cell-mediated cytotoxicity (Step 2). In Step 3, NK cells secrete growth factors (CCL3 and CCL4, among others) which may facilitate the growth of tumor cells (Step 4a). Alternatively, the lipids may preclude DCs lysis by NK cells which may result in stimulating the immune response (Step 4b)