CD151 dynamics in carcinoma–stroma interaction: integrin expression, adhesion strength and proteolytic activity

Abstract

A member of tetraspanin CD151 is a scaffold protein of laminin-binding integrins and it plays an important role in stable interaction between cells and basement membrane. Although the upregulation of CD151 in tumor cells is thought to accelerate tumor invasion and metastasis, detailed pathological investigation on CD151 and its association with integrins has not been well documented, yet. In the present study, we showed that the expression levels of CD151 and its associated integrin subunits in epidermal carcinoma cell HSC5 were higher than those in immortalized epidermal cell HaCaT. By the stimulation of epidermal growth factor, CD151 was dissociated from cell surface and dispersed in the cytoplasm, and a3b1 integrin was concomitantly internalized. To understand the significance of CD151 in tumor cell dynamics, CD151 in HSC5 was knocked down (HSC5 CD151À ), and the expression of integrin subunits and matrix metalloproteinases (MMPs) were investigated. In HSC5 CD151À, striking morphological alteration on Matrigel and laminin, and cytoskeletal rearrangements were demonstrated. a3b1 integrin was internalized in part, and a6b4 integrin was re-distributed from basal site to cell periphery. Quantitative RT-PCR, Western blot and zymography revealed that the expression levels of MMP2, MMP7 and MMP9 were markedly downregulated in HSC5 CD151À. Immunoprecipitation assay demonstrated that MMP7 was co-immunoprecipitated with CD151. In double stainings, MMP7 was colocalized with CD151 at the leading edge of lamellipodia under migratory status. These results elucidated the importance of CD151 as one of the key molecules for integrin-dependent carcinoma-stroma interaction. It is indicated that CD151 might contribute not only to cell stabilization by associating with adhesion complexes but also to cell migration by inducing integrins re-localization and MMPs production.

Tetraspanin CD151 regulates RhoA activation and the dynamic stability of carcinoma cell-cell contacts

“…Further support for this view comes from another recent study in which CD151 was silenced in H5SC carcinoma cells, resulting in redistribution of cortical actin and enhanced stress fibers (Hasegawa et al, 2007). Lastly, our results contrast with a recently published study that demonstrated decreased gap filling in vitro by MCF-10A cells treated with a CD151 siRNA (Yang et al, 2008).…”

“…For example, whereas tetraspanins CD9 and CD82 are potential metastasis suppressors (Boucheix et al, 2001;Lazo, 2007;Liu and Zhang, 2006;Tonoli and Barrett, 2005), tetraspanin CD151 has been linked to enhanced metastasis of colon, prostate and lung cancer (Ang et al, 2004;Hashida et al, 2003;Tokuhara et al, 2001). The mechanisms whereby tetraspanins might regulate metastasis can be grouped into several classes, including regulation of (i) pericellular matrix proteolysis (Gesierich et al, 2006;Hasegawa et al, 2007;Hong et al, 2006;Hong et al, 2005;Huang et al, 2007;Saito et al, 2006;Sugiura and Berditchevski, 1999), (ii) integrin cell-surface expression and trafficking (Berditchevski and Odintsova, 2007;Liu et al, 2007;Winterwood et al, 2006), (iii) integrin-dependent migration, invasion and signaling (Berditchevski, 2001;Hemler, 2005), (iv) integrin crosstalk with growth factor receptors (Sridhar and Miranti, 2006) and (v) pathological angiogenesis (Gesierich et al, 2006;Takeda et al, 2007). Most of these proposed tetraspanin functions center around regulation of cell-extracellular matrix interactions and downstream signaling events.…”

p53 expression in tumor-stromal fibroblasts forming and not forming fibrotic foci in invasive ductal carcinoma of the breast

“…1,2 In contrast, tumor-stromal fibroblasts not forming fibrotic foci commonly admix with many tumor cells that show stromal invasion. This difference p53 expression in tumor-stromal fibroblasts strongly suggests that the tumor cell-stromal cell interaction occurs more frequently in the outer area of a fibrotic focus than in the inner area of a fibrotic focus within IDCs, 10,11 probably resulting in the higher Allred scores for p53 in tumor-stromal fibroblasts not forming fibrotic foci. However, the Allred scores for p53 in tumor-stromal fibroblasts forming fibrotic foci were significantly associated with those for p53 in tumor-stromal fibroblasts not forming fibrotic foci.…”

“…6,7 Because it has recently been reported that the gene expression profile and protein expression profile of the tumor stroma have a very important function in tumor progression in carcinoma 8,9 and that the interactions between tumor cells and stromal cells also are very important in tumor progression in carcinomas, 10,11 these findings strongly suggest that the tumor stroma has a significant function in tumor progression in IDCs. Mutations of the p53 tumor suppressor gene have been described in the stromal fibroblasts of breast and prostate carcinomas in humans and experimental animals, [12][13][14] and p53 mutations in breast cancer stromal cells have been reported to be closely associated with nodal metastasis.…”

CD151 in cancer progression and metastasis: a complex scenario

“…MMP-7 activity was also confirmed around the human lung adenocarcinoma cell nests, the sites of CD151 and MMP-7 colocalization. 61,62 However, reported by Shiomi et al a remarkably strong interaction of CD151 with pro-MMP-7, observed even in stringent conditions, has not been so far confirmed by other groups. Moreover, presented recovery of interaction was supposed to involve the large extracellular loop (EC2) of CD151.…”