Conditional ROCK Activation <b>
                     <i>In vivo</i>
                  </b> Induces Tumor Cell Dissemination and Angiogenesis

Croft, Daniel R.; Sahai, Erik; Mavria, Georgia; Li, Shuixing; Tsai, Jeff H.; Lee, William M. F.; Marshall, Christopher J.; Olson, Michael F.

doi:10.1158/0008-5472.can-04-2052

Cited by 154 publications

(125 citation statements)

References 47 publications

(48 reference statements)

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“…Despite increased protrusion, inhibition of Rho or ROCK leads to decreased motility in 2D culture, consistent with data from colon cancer cells [51] but different from studies in MDA-MB-231 adenocarcinoma cells [52]. The loss of motility in C3T-or Y27632-treated MTLn3 cells could be in part due to excessive Rac activation, as expression of a constitutively active Rac mutant in MTLn3 (Table 2) and other cells lines [53] leads to a symmetrical, circumferential protrusion and decreased motility.…”

Section: Discussionsupporting

confidence: 88%

RhoA/ROCK-mediated switching between Cdc42- and Rac1-dependent protrusion in MTLn3 carcinoma cells

El‐Sibai

Pertz

Pang

et al. 2008

Experimental Cell Research

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Rho GTPases are versatile regulators of cell shape that act on the actin cytoskeleton. Studies using Rho GTPase mutants have shown that, in some cells, Rac1 and Cdc42 regulate the formation of lamellipodia and filopodia, respectively at the leading edge, whereas RhoA mediates contraction at the rear of moving cells. However, recent reports have described a zone of RhoA/ROCK activation at the front of cells undergoing motility. In this study, we use a FRET-based RhoA biosensor to show that RhoA activation localizes to the leading edge of EGF-stimulated cells. Inhibition of Rho or ROCK enhanced protrusion, yet markedly inhibited cell motility; these changes correlated with a marked activation of Rac-1 at the cell edge. Surprisingly, whereas EGF-stimulated protrusion in control MTLn3 cells is Rac-independent and Cdc42-dependent, the opposite pattern is observed in MTLn3 cells after inhibition of ROCK. Thus, Rho and ROCK suppress Rac-1 activation at the leading edge, and inhibition of ROCK causes a switch between Cdc42 and Rac-1 as the dominant Rho GTPase driving protrusion in carcinoma cells. These data describe a novel role for Rho in coordinating signaling by Rac and Cdc42.

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Section: Discussionsupporting

confidence: 88%

RhoA/ROCK-mediated switching between Cdc42- and Rac1-dependent protrusion in MTLn3 carcinoma cells

El‐Sibai

Pertz

Pang

et al. 2008

Experimental Cell Research

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“…These data suggest that FZD7 may be important in the invasion and metastasis of CRC. Recent studies have shown that non-canonical Wnt signalling pathways affect the motility and invasion of cancer cells (Weeraratna et al, 2002;Croft et al, 2004;Qiang et al, 2005), but there is little data on CRC cells. Although there is a report that conditional ROCK activation of colon cancer cells induced in vitro motility and in vivo tumour cell dissemination in nude mice (Croft et al, 2004), the relation of FZD7 with non-canonical signals in CRC cells remains unknown.…”

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confidence: 99%

Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells

et al. 2009

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BACKGROUND: The canonical Wnt signalling pathway is activated in most sporadic colorectal cancers (CRCs). We previously reported that FZD7 functions as a receptor for the canonical Wnt signalling pathway in colon cancer cells. METHODS AND RESULTS: In this study, we examined the function of FZD7 in survival, invasion and metastatic capabilities of colon cancer cells. FZD7_siRNA transfection decreased cell viability of HT-29 and HCT-116 colon cancer cells. Expression of c-Jun, phosphorylation of JNK and c-Jun, and activation of RhoA were suppressed after FZD7_siRNA transfection into HCT-116 cells. In vitro invasion activity and Wnt target gene expression were also reduced in HCT-116 cells transfected with FZD7_siRNA. Liver metastasis of stable FZD7_siRNA HCT-116 cell transfectants in scid mice was decreased to 40 -50% compared to controls. The mRNA levels of FZD7 in 135 primary CRC tissues were examined by real-time PCR. FZD7 mRNA levels were significantly higher in stage II, III or IV tumours than in non-tumour tissues (Po0.005), and overall survival was shorter in those patients with higher FZD7 expression (Po0.001). CONCLUSION: These data suggest that FZD7 may be involved in enhancement of survival, invasion and metastatic capabilities of colon cancer cells through non-canonical Wnt signalling pathways as well as the canonical pathway.

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“…This reduction in cell-cell adhesion promotes movement and allows for migration of endothelial cells into the tumor, a process that may lead to the formation of new vascular channels. 10 Furthermore, when ROCK-II is activated in in vitro colon cancer cell models it produced greater instability at the sites of adherens junction formation. 9 While these studies have provided important information about the contribution of ROCK-II to the disruption of adherens junctions in colon cancer, they do not fully answer the question of how it contributes to invasion in colon cancer.…”

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confidence: 99%

ROCK-II mediates colon cancer invasion via regulation of MMP-2 and MMP-13 at the site of invadopodia as revealed by multiphoton imaging

Vishnubhotla

Sun

Huq

et al. 2007

Laboratory Investigation

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The ROCK-II isoform of Rho's downstream effector, Rho kinase, has been linked with greater invasion and metastasis in solid tumors. We have previously shown that ROCK-II is overexpressed at the advancing edge of colon cancers. The mechanism whereby ROCK-II contributes invasion, particularly in the setting of colon cancer, remains to be elucidated fully. To better understand its contribution, we evaluated ROCK-II expression in both non-malignant (NCM460 and IEC-6) and malignant (Caco-2 E, SW620, and HCT-116) intestinal epithelial cell lines grown in type I collagen scaffolds. Using multiphoton microscopy, we observed that ROCK-II localized to the actin cytoskeleton in non-malignant cells but localized to the cell periphery as focal collections with an absence of adjacent collagen in all colon cancer cell lines. By transmission electron microscopy, these collections corresponded with finger-like projections previously described as invadopodia. Immunogold staining with cortactin, matrix metalloprotease (MMP)-2, -9, and -13 confirmed that these were indeed invadopodia. To further link ROCK-II to colon cancer invasion, we treated non-malignant and malignant intestinal epithelial cell lines with ROCK-II siRNA and evaluated depth of invasion, proliferation, and MMP-2, -9, and -13 activities. The most striking effect was seen in the highly tumorigenic cell lines, SW620 and HCT-116, wherein ROCK-II knockdown resulted in a two-fold or more reduction in invasion. This reduction in invasion was not due to a decrease in cell proliferation, as a significant reduction in proliferation was only observed in the two non-malignant intestinal cell lines. Finally, both MMP-2 and -13 activities were significantly decreased in all colon cancer cell lines. Taken together, these data suggest for the first time that ROCK-II is a critical mediator of colon cancer cell invasion through its modulation of MMP-2 and -13 at the site of invadopodia but regulates proliferation in non-malignant intestinal cells.

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Conditional ROCK Activation In vivo Induces Tumor Cell Dissemination and Angiogenesis

Abstract: ABSTRACT

Cited by 154 publications

References 47 publications

RhoA/ROCK-mediated switching between Cdc42- and Rac1-dependent protrusion in MTLn3 carcinoma cells

RhoA/ROCK-mediated switching between Cdc42- and Rac1-dependent protrusion in MTLn3 carcinoma cells

Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells

ROCK-II mediates colon cancer invasion via regulation of MMP-2 and MMP-13 at the site of invadopodia as revealed by multiphoton imaging

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