Tumor invasion in the absence of epithelial-mesenchymal transition: Podoplanin-mediated remodeling of the actin cytoskeleton

Abstract

The expression of podoplanin, a small mucin-like protein, is upregulated in the invasive front of a number of human carcinomas. We have investigated podoplanin function in cultured human breast cancer cells, in a mouse model of pancreatic beta cell carcinogenesis, and in human cancer biopsies. Our results indicate that podoplanin promotes tumor cell invasion in vitro and in vivo. Notably, the expression and subcellular localization of epithelial markers are unaltered, and mesenchymal markers are not induced in invasive podoplanin-expressing tumor cells. Rather, podoplanin induces collective cell migration by filopodia formation via the downregulation of the activities of small Rho family GTPases. In conclusion, podoplanin induces an alternative pathway of tumor cell invasion in the absence of epithelial-mesenchymal transition (EMT).

The potential role of podoplanin in tumour invasion

“…In this model, podoplanin shifted the invasion pattern from single cell invasion involving EMT to the invasion of large cell sheets in the absence of EMT. This notion is supported by the finding that forced expression of podoplanin in MCF7 cells did not induce a cadherin-switch or EMT, although the cells formed filopodia and became more migratory and invasive (Wicki et al, 2006). However, although most b-cell tumours did not undergo a cadherin switch in podoplanin-expressing Rip1Tag2 tumour cells, a subset of the tumours lost E-cadherin expression.…”

“…The expression of podoplanin is upregulated in a number of different human cancers, including squamous cell carcinoma of the oral cavity, the larynx, the lung, the cervix, the oesophagus, and the skin, in dysgerminomas of the ovary and granulosa cell tumours, in mesothelioma, and in many tumours of the central nervous system (CNS) (Kato et al, 2005;Kimura and Kimura, 2005;Martin-Villar et al, 2005;Schacht et al, 2005;Shibahara et al, 2006;Wicki et al, 2006). The oncofetal M2A antigen expressed in testicular germ cell tumours is identical to podoplanin (Dumoff et al, 2005).…”

“…For example, nuclear localisation of b-catenin and upregulation of b 1 -integrin and the L1 cell adhesion molecule were specifically observed in cells of the invasive tumour front (Brabletz et al, 2001;Hegerfeldt et al, 2002;Gavert et al, 2005). We have recently reported that in about 80% of human squamous cell carcinomas (lung, larynx, cervix, skin and oesophagus) podoplanin is expressed -often in a one-cell layer -at the invasive edge of the tumours (Wicki et al, 2006). In Figure 1, a cancer with single cell invasion (panel A) is compared to a tumour with a collectivecell invasion pattern (panel B).…”

“…The restricted expression of podoplanin at the front of human squamous cell carcinomas prompted the question whether factors of the surrounding tissue could influence podoplanin expression. Indeed, podoplanin expression can be induced by epidermal growth factor, basic fibroblast growth factor (FGF2) and tumour necrosis factor a in MCF7 breast cancer cells, and by bradykinin in 3T3 fibroblasts (Scholl et al, 1999;Wicki et al, 2006). Thus, podoplanin expression may be modulated by the environment of the tumour.…”

“…Recent experimental results have demonstrated that podoplanin, a small mucin-like protein, mediates a pathway leading to collective cell migration and invasion in vivo and in vitro (Wicki et al, 2006). In this review, we will focus on the molecular basis underlying the phenomenon of cell invasion induced by podoplanin, and discuss potential implications for cancer diagnosis and treatment.…”