Abstract
Fibronectin (FN) expressed by tumor cells has been known to be tumor suppressive but the pericellular FN (periFN) assembled on circulating tumor cells appears to evidently promote distant metastasis. Whereas the regulation of periFN assembly in suspended cells has currently been under investigation, how it is regulated in adherent tumor cells and the role of periFN in primary tumor growth remain elusive. Techniques of RNAi, plasmid transfections, immunoblotting, fluorescence/immunohistochemistry staining, cell proliferation assays, and primary tumor growth in C57BL6 mice and Fischer 344 rats were employed in this study. We found that endogenously synthesized FN in adherent tumor cells was required for periFN assembly which was aligned by RhoA-organized actin stress fiber (SF). Depleting periFN on adherent tumor cells congruently promoted in vivo tumor growth but surprisingly did not autonomously impact on in vitro tumor cell proliferation and apoptosis, suggestive of a non-autonomous role of periFN in in vivo tumor growth. We showed that the proliferative ability of shFN-expressing tumor cells was higher than shScramble cells did in the presence of fibroblasts. Altogether, these results suggested that depriving RhoA/SF-regulated periFN matrices non-autonomously promotes fibroblast-mediated tumor cell growth.
Highlights
Metastasis is responsible for major cancer death [1,2]
We quantitatively found that endogenous FN expressions and the levels of pericellular FN (periFN) assembly were significantly higher in the control shScr-MTF7 cells (Figure 1a and Figure 1c, respectively) and shScr-Lewis lung carcinoma (LLC) cells (Figure 1d and Figure 1f, respectively) than in shFN-silenced MTF7 and LLC cells
It seems relatively controversial that periFN promotes cancer metastasis but serves as a tumor suppressor to decrease primary tumor cell proliferation [1]
Summary
Metastasis is responsible for major cancer death [1,2]. Tumor cells initiate from normal, often epithelial, cells, the apoptotic and proliferative activities of which are dysregulated through oncogenic activation or inactivation by tumor suppressors and progress all the way from primary tissues to distant organs where they establish metastatic growth, which are autonomously and non-autonomously regulated in a temporal and spatial manner [1,3]. It has recently been reported that pericellular FN (periFN) assembled on circulating cell surfaces promotes tumor colonization, extravasation, and metastatic growth in lungs [9,10,11,12,13]. Abundant evidence shows that matrixdepositing FN polymers to which tumor cells adhere promote their proliferative activities [19,20,21,22]. Numerous reports have demonstrated that silencing or decreasing endogenous FN expression greatly enhances tumor growth [23,24,25,26,27], implicating that FN synthesized by tumor cells plays an inhibitory role in tumor cell proliferation. The regulations of periFN assembled on adherent normal cells [30,31,32,33] and suspended tumor cells [11,12,13] have been explored, how it is regulated on adherent tumor cells and whether it is autonomously involved in tumor proliferation and in vivo tumor growth are, less clear
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