Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

Abstract

Milk fat globule-epidermal growth factor-factor VIII (MFGE8), also called lactadherin or SED1, is a secreted integrin-binding protein that promotes elimination of apoptotic cells by phagocytes leading to tolerogenic immune responses, and vascular endothelial growth factor (VEGF)-induced angiogenesis: two important processes for cancer development. Here, by transcriptomic analysis of 228 biopsies of bladder carcinomas, we observed overexpression of MFGE8 during tumor development, correlated with expression of genes involved in cell adhesion or migration and in immune responses, but not in VEGF-mediated angiogenesis. To test whether MFGE8 expression was instrumental in bladder tumor development, or a simple consequence of this development, we used genetic ablation in a mouse model of carcinogen-induced bladder carcinoma. We showed that Mfge8 was also upregulated in mouse carcinoma, and that in its absence, Mfge8-deficient animals developed less advanced tumors. Angiogenesis was similar in carcinogen-treated Mfge8-expressing or -deficient bladders, thus ruling out a major role of the proangiogenic function of Mfge8 for its protumoral role. By contrast, the tumorpromoting role of Mfge8 was not observed anymore in mice devoid of adaptive immune system, and human tumors overexpressing MFGE8 where invaded with macrophages and regulatory T cells, thus suggesting that MFGE8/ lactadherin favors development of bladder tumors at least partly by an immune system-dependent mechanism. Our observations suggest future use of MFGE8-inhibiting molecules as therapies of bladder carcinomas, and of a limited number of other human cancers, in which our analysis of public databases also revealed overexpression of MFGE8.

Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells

“…(B) In vivo serial tumor passages were performed to evaluate the frequency of CSCs. TAM from wild-type or MFG-E8-deficient mice was injected along with MC38-CSCs s.c. into MFG-E8-deficient mice (n = 4 per group) at 1 × immune-dependent mechanisms (10,11,23). In this study, we have identified that MFG-E8, mainly derived from CSC-associated macrophages, is a major contributor in triggering the tumorigenicity and resistance to anticancer drugs of CSCs.…”

“…Although MFG-E8 has been reported to accelerate tumorigenicity of certain spontaneously arising tumors (23), it remains unknown whether MFG-E8 modulates CSC functions. Thus, MC38-CSCs or 3LL-CSCs were inoculated into MFG-E8-deficient mice or their wild-type counterparts, and the CSC frequencies in established tumors were evaluated by measuring CSC-specific marker expression 1 mo after in vivo tumor challenge.…”

MFG-E8 expression for progression of oral squamous cell carcinoma and for self-clearance of apoptotic cells

“…14 Angiogenic endothelial cells in and around the tumor have MFG-E8-dependent phagocytic properties for apoptotic cells or aged erythrocytes. 15 In addition to phagocytotic events, the MFG-E8 expressions are also known to be upregulated in neoplastic conditions, including breast cancer, 1,16,17 malignant melanoma, 18,19 bladder tumors, 20 and ovarian cancer. 21 The MFG-E8 expression has been correlated to their progressions [18][19][20] and to poor clinical outcome.…”

“…15 In addition to phagocytotic events, the MFG-E8 expressions are also known to be upregulated in neoplastic conditions, including breast cancer, 1,16,17 malignant melanoma, 18,19 bladder tumors, 20 and ovarian cancer. 21 The MFG-E8 expression has been correlated to their progressions [18][19][20] and to poor clinical outcome. 19 Regarding neoplasms of keratinocytic origin, MFG-E8 has been demonstrated in experimentally induced skin tumors in mice, in which the reduced expression of MFG-E8 was correlated with cellular differentiation.…”

Animal Models for Basic and Preclinical Research in Bladder Cancer

“…This problem will soon be overcome by the design of non-invasive diagnostic equipment for small animals, similar to those used in medical practice in humans, such as ultrasound-doppler, infrared (IR) or bioluminescence imaging. By way of example, ultrasound-Doppler sagittal images have been used to evaluate angiogenesis in a mouse bladder cancer model (Sugano et al, 2011). Also, bladder cancer cells that have been engineered to express certain proteins that emit fluorescence are being used in bioluminescence detection of tumor development (Black et al, 2010).…”