Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti‐inflammatory phenotype

Abstract

A challenging task of the immune system is to fight cancer cells. However, a variety of human cancers educate immune cells to become tumor supportive. This is exemplified for tumor-associated macrophages (TAMs), which are polarized towards an antiinflammatory and cancer promoting phenotype. Mechanistic explanations, how cancer cells influence the macrophage phenotype are urgently needed to address potential anti-cancer strategies along this line. One potential immune modulating compound, sphingosine-1-phosphate (S1P), was recently highlighted in both tumor growth and immune modulation. Using a xenograft model in nude mice, we demonstrate a supportive role of sphingosine kinase 2 (SphK2), one of the S1P-producing enzymes for tumor progression. The growth of SphK2-deficient MCF-7 breast tumor xenografts was markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors was comparable. However, TAMs from SphK2-deficient tumors displayed a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-a, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206. These data suggest a role for S1P, generated by SphK2, in early tumor development by affecting macrophage polarization. ' 2009 UICC

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…This result is contradictory with those of previous studies 6, 19, 23, 24. We discuss this inconsistency in the following.…”

“…It is also a chemotactic factor for immune cell trafficking 5, 16, 17 and a microenvironmental regulator for cancer development 18. The growth rate of breast cancer cells was found to be decreased in SPHK1 or SPHK2 deficient mice 19. Based on these observations, S1P promote breast cancer (BCA) development was hypothesized.…”

Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions

“…For example, high production of IL-10 and low production of IL-12 is seen as a hallmark of all non-M1 macrophages, and is also applicable to most TAM populations in different cancer types. Also in breast cancer, high in vivo IL-10 production has been reported and is linked to reduced immune responsiveness (Guiducci et al, 2005;Weigert et al, 2009;PuigKröger et al, 2009). A skewing of the L-arginine metabolism towards higher arginase-1-mediated and lower iNOS-mediated L-arginine consumption is another typical feature of anti-inflammatory macrophages, at least in mice.…”

“…Hsp27-differentiated macrophages induce unresponsiveness in T cells and are strongly proangiogenic (Banerjee et al, 2011). In addition, dying cancer cells secrete sphingosine-1-phosphate (S1P) and TGF-b that polarize macrophages towards an anti-inflammatory phenotype (Herr et al, 2009;Weigert et al, 2009). A knockdown of sphingosine kinase 2, the enzyme responsible for S1P production, in human MCF-7 breast cancer cells strongly impairs tumor xenograft growth associated with a deficiency in anti-inflammatory TAM generation .…”

Roles of sphingosine 1-phosphate on tumorigenesis

“…Likewise, knockdown of SphK2 inhibits cell proliferation in U14242 and U87 MG glioblastoma cells [76] . Moreover, the growth of SphK2-deficient MCF-7 breast tumor xenografts is markedly delayed and displays a prominent anti-tumor phenotype, based on the observation of increasing expression of pro-inflammatory mediators such as NO, TNF-alpha, IL-12 and MHCII, and lower expression of anti-inflammatory IL-10 and CD206 [87] . These observations suggest that either exogenous S1P mediated through its cell surface receptors or intracellular S1P produced by SphKs is important for cell proliferation.…”