Key proteins of invadopodia are overexpressed in oral squamous cell carcinoma suggesting an important role of MT1-MMP in the tumoral progression

Abstract

Background Oral squamous cell carcinoma (OSCC) is the most relevant malignant neoplasm among all head and neck tumours due to its high prevalence and unfavourable prognosis. Tumour invasion and metastasis that affect prognosis are result of a set of complex events that cells with invasive potential use to spread to other regions. These cells use several mechanisms to invade tissues, including a type of finger-like membrane protrusion called invadopodia. This study aims to investigate the immunoexpression of invaopodia related-proteins TKs5, cortactin, TKs4 and MT1-MMP in OSCC and correlate it to clinicopathological data. Methods An immunohistochemical evaluation of fifty cases of OSCCs and 20 cases of oral mucosa (OM) were assessed. The expression of invadopodia proteins were analysed in comparison to normal tissue (OM) and correlated to different clinical-stage and histological grade of OSCC. Results TKs5, cortactin, TKs4 and MT1-MMP were significantly overexpressed in OSCC when compared to OM (p < 0.0001). Among tumour stages, TKs5 showed a statistical difference in immunolabelling between stage I and III (p = 0.026). Cortactin immunolabelling was statistically higher in grade I than in grade II and III. No differences were seen on TKs4 expression based on tumour staging or grading. MT1-MMP was higher expressed and showed statistical difference between stages I and III and grades I compared to II and III. Conclusions The invadopodia related-proteins were found to be overexpressed in OSCC when compared to OM, suggesting invadopodia formation and activity. Besides overexpressed in OSCC, cortactin, TKs4 and TKs5 showed no or ambiguous differences in protein expression when compared among clinical-stages or histological grades groups. Conversely, the expression of MT1-MMP increased in advanced stages and less differentiated tumours, suggesting MT1-MMP expression as a promising prognostic marker in OSCC.

Absence of Scaffold Protein Tks4 Disrupts Several Signaling Pathways in Colon Cancer Cells

“…Multiple pieces of evidence indicate the involvement of Tks4 in the pathogenesis of different cancers. As a result of its role in podosome formation, it has been suggested to increase metastatic capability of oral squamous cell carcinoma [ 23 ], hepatocellular carcinoma (HCC) [ 24 ], melanoma [ 22 ], and lung cancer [ 25 ]. Tks4 also appears to be involved in the reactive oxygen species generation and invadopodia formation in colon cancer [ 26 ].…”

The Multiple Roles of CD147 in the Development and Progression of Oral Squamous Cell Carcinoma: An Overview

“…Among them, the best-known is its effective participation in the remodeling of the ECM, which occurs during physiologic tissue growth, maturation, and/or repair, but also in pathologic settings such as chronic inflammatory diseases and tumors [ 26 ]. CD147’s effects on the ECM are due to CD147’s ability to interact with cell-matrix adhesion receptors, for example, integrins [ 40 , 41 ], and to activate ECM-degrading proteolytic enzymes such as MMPs ( Table 2 ) [ 26 , 38 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

“…Among CD147-induced MMPs, MMP-1 mediates the initial phase of OSCC invasion because of its capability of degrading both cell-to-cell adhesion molecules as well as the peri-tumoral matrix ( Table 2 ) [ 18 ]. Further MMPs whose synthesis is promoted upon CD147 activation are MMP-2, MMP-9, and membrane type (MT)1-MMP ( Table 2 ) [ 42 , 43 , 44 ], whose levels positively correlate with the size, histological grade, or stage of progression of OSCC, and are predictive of its metastatization [ 31 , 84 , 85 , 86 , 87 ].…”

“…To infiltrate the tissues and move through them, cancer cells rearrange their cytoskeleton so that their plasma membrane ejects and generates protruding structures called invadopodia [ 44 , 88 ]. In this context, CD147 cooperates with growth factors to induce the formation of invadopodia in epithelial cells [ 89 , 90 ].…”

“…Of interest, invadopodia are present not only in OSCCs but also in OPMDs at high risk of neoplastic transformation [ 88 ]. In both premalignant and malignant oral lesions, CD147 is positioned on the leading edge of the invadopodia together with MT1-MMP, which, after being activated by CD147, degrades ECM both directly and by converting latent MMP-2 and MMP-9 in their active forms [ 26 , 44 , 91 ]. At the same time, CD147 stimulates CAFs to synthesize tenascin-C ( Table 2 ) [ 49 ], an ECM molecule that facilitates OSCC cell migration [ 20 ].…”