Nitric Oxide Regulates Tumor Cell Cross-Talk with Stromal Cells in the Tumor Microenvironment of the Liver

Decker, Ningling Kang; Abdelmoneim, Soha Saoud; Yaqoob, Usman; Hendrickson, Helen; Hormes, Joe; Bentley, Michael J.; Pitot, Henry C.; Urrutia, Raúl; Gores, G. J.; Shah, Vijay H.

doi:10.2353/ajpath.2008.080158

Cited by 42 publications

(45 citation statements)

References 39 publications

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“…Type IV collagen increases tumor cell resistance to anoikis The ECM provides survival signals to the cells and has been linked to the ability of tumor cells to evade cell detachment-induced apoptosis (anoikis) and metastasize (Eccles and Welch, 2007;Decker et al, 2008;Simpson et al, 2008). Liver metastasis, in particular, was shown to be associated with an increased cell capacity to resist anoikis (Duxbury et al, 2004).…”

Section: Col3a1mentioning

confidence: 99%

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

et al. 2011

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The liver is a major site of metastasis for human malignancies, yet the factors that regulate tumor cell survival and growth in this organ remain elusive. Previously, we reported that M-27 IGFÀIR murine lung carcinoma cells with ectopic insulin-like growth factor-1 (IGF-I) receptor overexpression acquired a site-specific, liver-metastasizing potential. Gene expression profiling and subsequent RNA and protein analyses revealed that this was associated with major changes to the expression of extracellular matrix (ECM) protein-encoding genes including type III, IV and XVIII collagen genes, and these changes were also observed in the respective tumors in vivo. Because type IV collagen was the most prominently altered ECM protein in this model, we further analyzed its functional relevance to liver metastasis. M-27 cells stably overexpressing type IV collagen a1 and a2 chains were generated and their growth and metastatic properties investigated. We found that these cells acquired a site-selective growth advantage in the liver and this was associated with cell rescue from anoikis in a collagen IV/a2 integrin/FAK-dependent manner and increased responsiveness to IGF-I. Conversely, collagen IV or focal adhesion kinase (FAK) silencing by smallinterfering RNA in highly metastatic tumor cells enhanced anoikis and decreased liver metastases formation. Moreover, analysis of human surgical specimens revealed uniformly high collagen IV expression in 65/65 hepatic metastases analyzed, regardless of tissue of origin, whereas it was variable and generally low in 50/50 primary colorectal carcinoma specimens examined. The results suggest that collagen IV-conveyed signals are essential cues for liver metastasis in diverse tumor types and identify mediators of collagen IV signaling as potential therapeutic targets in the management of hepatic metastases.

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Section: Col3a1mentioning

confidence: 99%

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

et al. 2011

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“…In this regard, a potential modulatory impact of Nitric oxide (NO) on the activty and/or expression of Fox-factors in tumor cells may be of interest. NO signaling has been implicated in the complex inter-communication of tumor cells and respective stromal cells, affecting tumor progression and tumor cell invasion, 58 as well as epithelial cell differentiation of prostate cancer cell lines by repressing the transcription factor Snail1 and a subsequent increase in expression of the metastasis inhibitor RKIP. 59 It is further vital to substantiate the impact of Fox-factors in relation to cell plasticity of carcinoma cells in actual tumor samples (in vivo).…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

Forkhead factors regulate epithelial plasticity: Impact on cancer progression

2011

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“…After beads were washed 4 times, precipitated proteins were eluted with Laemmli sample buffer (Bio-Rad) and loaded onto PAGE gels for WB. Immunoblotting was done as we previously described (55). Densitometry was performed by the ImageJ software (NIH).…”

Section: Figure 14mentioning

confidence: 99%

IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver

Liu

Billadeau²,

Abdelhakim³

et al. 2013

J. Clin. Invest.

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149

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In the tumor microenvironment, TGF-β induces transdifferentiation of quiescent pericytes and related stromal cells into myofibroblasts that promote tumor growth and metastasis. The mechanisms governing myofibroblastic activation remain poorly understood, and its role in the tumor microenvironment has not been explored. Here, we demonstrate that IQ motif containing GTPase activating protein 1 (IQGAP1) binds to TGF-β receptor II (TβRII) and suppresses TβRII-mediated signaling in pericytes to prevent myofibroblastic differentiation in the tumor microenvironment. We found that TGF-β1 recruited IQGAP1 to TβRII in hepatic stellate cells (HSCs), the resident liver pericytes. Iqgap1 knockdown inhibited the targeting of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor 1 (SMURF1) to the plasma membrane and TβRII ubiquitination and degradation. Thus, Iqgap1 knockdown stabilized TβRII and potentiated TGF-β1 transdifferentiation of pericytes into myofibroblasts in vitro. Iqgap1 deficiency in HSCs promoted myofibroblast activation, tumor implantation, and metastatic growth in mice via upregulation of paracrine signaling molecules. Additionally, we found that IQGAP1 expression was downregulated in myofibroblasts associated with human colorectal liver metastases. Taken together, our studies demonstrate that IQGAP1 in the tumor microenvironment suppresses TβRII and TGF-β dependent myofibroblastic differentiation to constrain tumor growth.

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Nitric Oxide Regulates Tumor Cell Cross-Talk with Stromal Cells in the Tumor Microenvironment of the Liver

Cited by 42 publications

References 39 publications

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

Forkhead factors regulate epithelial plasticity: Impact on cancer progression

IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver

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