Abstract
Only recently low-grade serous carcinoma (LGSOC) of the ovary has been recognized as a disease entity distinct from the more common high-grade serous carcinoma (HGSOC), with significant differences in pathogenesis and clinical and pathologic features. The present study aimed at evaluating whether the different natural histories and patterns of response to therapy demonstrated for LGSOC and HGSOC, along with a diverse genomic landscape, may also reside in the supporting tumor stroma, specifically in the state of differentiation and activation of tumor associated macrophages (TAMs). TAMs play complex roles in tumorigenesis since they are believed to possess both tumor rejecting (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we showed that, when compared to HGSOC (n = 55), LGSOC patients (n = 25) exhibited lower density of tumor-infiltrating CD68+ macrophage, along with an attenuated M2-skewed (CD163+) phenotype. Accordingly, assessment of intratumoral vascularization and of matrix metalloproteinase 9 expression (a key protein involved in tumor invasion and metastasis) revealed lower expression in LGSOC compared to HGSOC patients, in line with emerging evidence supporting a role for TAMs in all aspects of tumor initiation, growth, and development. In conclusion, results from the present study demonstrate that microenvironmental factors contribute greatly to determine clinical and pathological features that differentiate low and high grade serous ovarian carcinomas. This understanding may increase possibilities and opportunities to improve disease control and design new therapeutic strategies.
Highlights
Ovarian cancer is the most deadly gynecologic malignancy [1]
Significant clinical, pathologic, and pathogenesis differences have been described between low-grade serous carcinoma (LGSOC) and high-grade serous carcinoma (HGSOC), most research on the diversity of these two cancers has been focused on the impact of cancer cell biology [9]
We show here, for the first time, that LGSOC and HGSOC exhibit striking differences in tumorassociated macrophage infiltration and, more importantly, in their activation profile, findings which were in turn related to different tumor vascularization and expression of key proteins involved in tumor growth and metastases
Summary
Ovarian cancer is the most deadly gynecologic malignancy [1] This insidious disease is often diagnosed in an advanced stage, develops rapidly and has a poor prognosis. In line with the evidence that ovarian cancer represents a group of distinct entities with distinct types of carcinogenesis, it is widely accepted that low-grade and high-grade serous tumors are essentially distinct diseases, exhibiting distinct genetic alterations, molecular patterns and clinical behaviors. The former develop from wellrecognized precursors and behave in an indolent fashion, are characterized by specific mutations, including KRAS, www.impactjournals.com/oncotarget
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