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. 2022 Jun 4;14(11):2790.
doi: 10.3390/cancers14112790.

High Levels of MFG-E8 Confer a Good Prognosis in Prostate and Renal Cancer Patients

Karen Geoffroy  1 , Patrick Laplante  1 , Sylvie Clairefond  1 , Feryel Azzi  1   2 , Dominique Trudel  1   2 , Jean-Baptiste Lattouf  1   3 , John Stagg  1   4 , Fred Saad  1   3 , Anne-Marie Mes-Masson  1   5 , Marie-Claude Bourgeois-Daigneault  1   6 , Jean-François Cailhier  1   5   7
Affiliations

High Levels of MFG-E8 Confer a Good Prognosis in Prostate and Renal Cancer Patients

Karen Geoffroy et al. Cancers (Basel). .

Abstract

Milk fat globule-epidermal growth factor-8 (MFG-E8) is a glycoprotein secreted by different cell types, including apoptotic cells and activated macrophages. MFG-E8 is highly expressed in a variety of cancers and is classically associated with tumor growth and poor patient prognosis through reprogramming of macrophages into the pro-tumoral/pro-angiogenic M2 phenotype. To date, correlations between levels of MFG-E8 and patient survival in prostate and renal cancers remain unclear. Here, we quantified MFG-E8 and CD68/CD206 expression by immunofluorescence staining in tissue microarrays constructed from renal (n = 190) and prostate (n = 274) cancer patient specimens. Percentages of MFG-E8-positive surface area were assessed in each patient core and Kaplan-Meier analyses were performed accordingly. We found that MFG-E8 was expressed more abundantly in malignant regions of prostate tissue and papillary renal cell carcinoma but was also increased in the normal adjacent regions in clear cell renal carcinoma. In addition, M2 tumor-associated macrophage staining was increased in the normal adjacent tissues compared to the malignant areas in renal cancer patients. Overall, high tissue expression of MFG-E8 was associated with less disease progression and better survival in prostate and renal cancer patients. Our observations provide new insights into tumoral MFG-E8 content and macrophage reprogramming in cancer.

Keywords: M2 macrophage; MFG-E8; prostate cancer; renal cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Expression of MFG-E8 in malignant areas of prostate and renal cancer tissues. Representative images of IF staining in prostate (A) and renal (B) cancer TMAs, grade 3 + 4 and grade 3, respectively. DAPI (blue) = nuclei, CK 8/18 (yellow) = epithelial cells, and MFG-E8 (red). The white boxes represent zoomed-in areas. Scale bars: 200 μm for whole image of sample, 50 µm for zoomed-in images. Images represent examples of high (top panels) and low (bottom panels) levels of MFG-E8 expression for both types of cancer.
Figure 2
Figure 2
Percentage of MFG-E8-positive surface in malignant and benign areas for prostate and renal cancer tissues. We compared the percentage of MFG-E8-positive staining in prostate cancer (a), CCRC (b), and PRCC (c) specimens in malignant (grey dots) and nonmalignant areas (benign/peripheral = white squares). Statistical analyses were performed using Mann–Whitney test: m = mean; ** p ≤ 0.01; **** p ≤ 0.0001.
Figure 3
Figure 3
Expression of MFG-E8 according to prostate and renal cancer grades.Comparison of the percentage of MFG-E8-positive staining between prostate cancer (a), CCRC (b), and PRCC (c) specimens with regards to cancer grade and malignancy. Statistical analyses were performed using one-way ANOVA test: m = mean; ns = not significant; * p ≤ 0.05 (3 + 3 vs. 4 + 4); *** p ≤ 0.001 (2 vs. 4).
Figure 4
Figure 4
M2 TAMs in renal cancer tissues. (a) Representative images of IF staining for CD68 and CD206 in renal cancer TMAs. DAPI (blue) = nuclei, CD68 (red), CD206 (yellow), and CK8/18 (green). Image panel on the right represents a zoom-in of the white box in the left image. Bar = 20 µm. CD68+/CD206+ cells (M2 macrophages) and CD68−/CD206+ cells were decreased in malignant areas (grey dots) compared with nonmalignant areas (white squares) in both CCRC (b) and PRCC (c). Statistical analyses were performed using two-sided Mann–Whitney test: m = mean; **** p ≤ 0.0001.
Figure 5
Figure 5
Patient survival according to MFG-E8 expression in prostate and renal cancer tissues. Kaplan–Meier analyses were performed for prostate (A) and renal (B) cancer patients based on the median value of MFG-E8 expression (classified as high (17%) and low (7.6%)). For prostate cancer, endpoints for analyses included biochemical recurrence (BCR), bone metastasis (BM), and overall survival (OS). For renal cancer, endpoints included progression-free survival (PFS) and OS. A value of p ≤ 0.05 was considered statistically significant.
Figure 6
Figure 6
Schematic diagram of our hypothesis. MFG-E8 is released as a soluble or vesicular protein by endothelial and epithelial cells within the tumor microenvironment. MFG-E8 exerts its pro-tumoral effects by promoting neoangiogenesis, epithelial-mesenchymal transition, and treatment resistance. In parallel, apoptotic endothelial (as we published) and renal epithelial cancer cells secrete MFG-E8 (as shown in the Western blot), and through various mechanisms discussed above, will favor M2 macrophage reprogramming or tumor-associated macrophages. Altogether, these mechanisms lead to a pro-tumoral microenvironment that is deleterious to cancer patients.
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