Abstract
BackgroundTumor-associated macrophages (TAMs) are classified into two major phenotypes, M1 and M2. M1 TAMs suppress cancer progression, while M2 TAMs promote it. However, little is known regarding the role of TAMs in the development of ovarian cancer. Here, we investigated the relationship between TAM distribution patterns (density, microlocalization, and differentiation) and ovarian cancer histotypes, and we explored whether altered TAM distribution patterns influence long-term outcomes in ovarian cancer patients.MethodsA total of 112 ovarian cancer patients were enrolled in this study, and the subjects were divided into two groups according to their survival (< 5 years vs. ≥ 5 years). Immunohistochemistry and immunofluorescence were used to determine the density, microlocalization, and differentiation status of TAMs in ovarian cancer tissues for each histotype. Kaplan-Meier survival and multivariate Cox regression analyses were used to evaluate the prognostic significance of TAM-related parameters in ovarian cancer.ResultsTAMs most frequently infiltrated into the cancer tissue of the serous histotype, followed by mucinous, undifferentiated, endometrioid, and clear cell histotypes (p = 0.049). The islet/stroma ratio of total TAMs varied among the cancer histotypes, with mucinous and undifferentiated cancers displaying the lowest and highest ratios, respectively (p = 0.005). The intratumoral TAM density significantly increased with increasing cancer stage and grade (p = 0.023 and 0.006, respectively). However, the overall M1/M2 TAM ratio decreased as the cancer stage increased (p = 0.012). In addition, the intra-islet M1/M2 ratio inversely correlated with the residual site size (p = 0.004). Among the TAM-related parameters, only the increased overall and intra-islet M1/M2 TAM ratios displayed prognostic significance in both the Kaplan-Meier survival and multivariate Cox regression analyses; however, the values of these two parameters did not differ significantly among the cancer histotypes.ConclusionsThe patients with increased overall or intra-islet M1/M2 TAM ratios presented with an improved 5-year prognosis. Nevertheless, the TAM distribution patterns did not influence the overall outcomes of different ovarian cancer histotypes.
Highlights
Tumor-associated macrophages (TAMs) are classified into two major phenotypes, M1 and M2
We aimed to address two core issues related to TAMs in ovarian cancer: (i) whether different histotypes of ovarian cancer are associated with different TAM distribution patterns and (ii) whether the altered TAM distribution patterns can confer different outcomes to ovarian cancer patients
In conclusion, the present study demonstrates that the overall and intra-islet M1/M2 ratios are effective TAM parameters to predict the outcomes of ovarian cancer patients, especially for those with a serous histotype
Summary
Tumor-associated macrophages (TAMs) are classified into two major phenotypes, M1 and M2. Immature macrophages infiltrate into cancer islets or their surrounding tissues (i.e., the cancer stroma) and can subsequently be activated to recognize and kill genetically mutated cancer cells [10,11]. These macrophages are called tumor-associated macrophages (TAMs) [12]. Cancer cells often secrete M2type cytokines such as IL-10, CCL2/3/4/5/7/8, CXCL12, VEGF, and platelet-derived growth factor (PDGF) to recruit monocytes/M0 macrophages and direct them toward an M2 phenotype [19,20]. M2 TAMs are frequently observed in cancer tissues [20]
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