Significance of podoplanin expression in cancer-associated fibroblasts: A comprehensive review

Abstract

Cancer-associated fibroblasts (CAFs) are well-known to be part of the tumor microenvironment. This heterogeneous population of cells of the tumor microenvironment via secretion of various growth factors and cytokines was shown to contribute to increased cancer cell proliferation rate, migration, invasiveness and other key processes such as angiogenesis and lymphangiogenesis. Recent studies identified podoplanin as a marker of CAFs in various malignancies and its expression in these cells was shown to influence cancer progression. In some studies it yielded a prognostic impact on patient survival which was strongly dependent on the entity of the tumor. This review summarizes recent findings concerning the biology of podoplanin in cancer progression with particular emphasis on its expression in CAFs.

Podoplanin-positive Cancer-associated Stromal Fibroblasts in Primary Tumor and Synchronous Lymph Node Metastases of HER2-overexpressing Breast Carcinomas

“…The results of the present study, obtained from a group of trastuzumab-treated patients with HER2-overexpressing breast cancer, confirmed the relationship between the presence of ppCAFs and ER/PR immunonegativity, and lymph node involvement, as well as the possible prognostic significance of podoplanin expression in CAFs (11,13,16,17). Correlation between the presence of ppCAFs and survival of trastuzumab-treated patients suggests that breast cancer stroma characteristics might influence sensitivity to trastuzumab-based adjuvant therapy.…”

“…Furthermore, it was suggested that CAFs might contribute to: (i) tumor initiation; (ii) proliferation, migration and invasiveness of cancer cells; (iii) tumor angiogenesis/lymphangiogenesis; (iv) tumor-induced inflammation; (v) metabolic reprogramming of the tumor microenvironment; and (vi) therapeutic resistance (4). Among many CAF-related proteins, podoplanin is one of the most intensively studied (8,9,(15)(16)(17) . Among breast cancer immunophenotypes, the human epidermal growth factor receptor 2 (HER2)-overexpressing subtype is the one in which ppCAFs were found to be relatively frequent (11).…”

New Insights into the Role of Podoplanin in Epithelial–Mesenchymal Transition

“…The interplay between tumor cells and the surrounding stroma is an accepted fact in today's cancer research taking his modern formulation in the work of Bissell et al (1982), and reviewed recently (Allen and Jones, 2011;Kalluri and Zeisberg, 2006;Pula et al, 2013 including its role in the recruitment of inflammatory cells into the tumor (Erez et al, 2010).…”

Podoplanin promotes malignancy through a diversity of strategies

“…cancer-associated fibroblasts (CAFs). We first observed the presence of PDPN in dermal fibroblasts during skin remodeling processes and in stromal fibroblast-like cells from chemically-induced mouse skin tumors [11] , and other laboratories have found the presence of this glycoprotein in fibroblasts of chronically inflamed tissues as well as in myofibroblast-like cells of different types of cancer [12,13] . Contradictory results have been reported about the prognostic value of PDPN expression in CAFs.…”

“…Contradictory results have been reported about the prognostic value of PDPN expression in CAFs. Thus, in lung adenocarcinomas, invasive ductal breast carcinomas, intrahepatic cholongiocarcinomas and esophagus adenocarcinomas, the presence of PDPN in CAFs is associated with shorter overall survival and poor prognosis, whereas it is considered as a favorable prognostic factor in colorectal cancer and without significant prognostic value in lung SCCs and uterine cervical carcinomas [1,12,13] . PDPN has a heavily O-glycosylated ectodomain, which confers a negative net charge to this moiety due to sialic acid modifications α2-3 to galactose and α2-6 to N-acetyl-galactosamine.…”