Differential Contribution to Neuroendocrine Tumorigenesis of Parallel Egfr Signaling in Cancer Cells and Pericytes

Nolan-Stevaux, Olivier; Truitt, Morgan C.; Pahler, Jessica C.; Olson, Peter; Guinto, Cristina D.; Lee, Dong Hoon; Hanahan, Douglas

doi:10.1177/1947601909358722

Cited by 24 publications

(24 citation statements)

References 56 publications

(94 reference statements)

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“…Furthermore, treatment with an inhibitor of EGFR signaling, gefitnib, induced apoptosis in RHAMM B -expressing cells, although we cannot exclude the possibility that this effect may be mediated by inhibition of other uncharacterized kinases. Additionally, it has been shown that EGFR signaling contributes to tumorigenesis in RIP-Tag mice (18). The RHAMM full-length isoform, RHAMM A , enhances serum-induced Erk1/2 phosphorylation in embryonic fibroblasts from RHAMM knockout mice (10), and here we showed that overexpression of RHAMM B phosphorylates Erk1/2 in mouse pancreatic islet tumor cells.…”

Section: Discussionsupporting

confidence: 67%

Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis

Chou

Klimstra

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The gene encoding the receptor for hyaluronan-mediated motility (RHAMM) is overexpressed in many human cancers. However, it is unclear whether RHAMM plays a causal role in tumor initiation or progression. Using somatic gene transfer in a mouse model of islet cell tumorigenesis, we demonstrate that RHAMM isoform B (RHAMM B ) promotes tumor growth and metastases to lymph nodes and the liver. The propensity of RHAMM B -expressing cells to metastasize to the liver was confirmed using an experimental metastasis assay in which cells were injected into the tail vein of immunodeficient mice. However, RHAMM B did not increase cell migration or proliferation in culture. In initial efforts to identify signaling pathways activated by RHAMM B , we found that RHAMM B induced phosphorylation of epidermal growth factor receptor (EGFR), Erk1/2, and STAT3 and conferred susceptibility to apoptosis after treatment with an EGFR inhibitor, gefitinib. Taken together, the results indicate that RHAMM B promotes hepatic metastasis by islet tumor cells, perhaps through growth factor receptor-mediated signaling. W e have previously reported a bitransgenic mouse model, RIP-Tag; RIP-tva, in which the rat insulin promoter (RIP) drives production of both the SV40 T antigen (RIP-Tag) and the receptor for subgroup A avian leukosis virus (RIP-tva) in pancreatic β cells (1). Coding domains of genes suspected of contributing to tumor progression can be introduced into premalignant lesions by infection with the avian retroviral vector, RCASBP, after intracardiac injection. RIP-Tag transgenic mice develop islet tumors through well-defined stages that resemble the progression of several kinds of human cancers; for this reason, we and others have used these mice, with or without additional transgenes, to identify and validate mechanisms of tumorigenesis that may operate in multiple tissues. For instance, we have used RIP-Tag; RIP-tva mice to show that RCASBPmediated delivery of Bcl-xL or E-cadherin, factors implicated in various neoplasms, promotes tumorigenesis and invasion in islet cells (1).High-throughput genomic technologies have identified many genes that may be critical in tumor initiation and progression. However, it remains difficult to distinguish causative and passenger mutations and to assign specific biological functions to altered genes in human cancers, and the RIP-Tag; RIP-tva mouse model of multistage tumorigenesis offers an opportunity to address such issues. To that end, we have assessed the oncogenic functions of a small number of incompletely characterized genes that are up-regulated in human hepatocellular carcinomas (HCC) and during mouse liver regeneration (2). One of the candidate genes, a gene encoding a receptor for hyaluronanmediated motility (RHAMM) is overexpressed in many types of human cancers, including pancreatic ductal carcinoma, hepatocellular carcinoma, multiple myeloma, breast cancer, gliomas, colon cancer, and prostate cancer (2-7); but the functions of at least four proteins encoded by its alternatively spliced m...

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Section: Discussionsupporting

confidence: 67%

Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis

Chou

Klimstra

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, increased activity of the EGFR pathway has been identified as a potential resistance mechanism (56,57). It is of note that in addition to dependence on IGF signaling, RIP-Tag2 tumors have also recently been demonstrated to exhibit sensitivity to pharmacological or genetic inactivation of EGFR (58), raising the possibility that signaling via EGFR can also influence the efficacy of IGF pathway targeting strategies in this model. It was surprising that effective blockade of IGF signaling pathways by A12 did not appreciably affect the invasive phenotype of the resultant tumors, in contrast to the proinvasive effects observed upon IGF-1R overexpression (20), perhaps suggesting that IGF-1R can enhance but is not obligatory for cancer cell invasion in this model.…”

Section: Discussionmentioning

confidence: 99%

Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy

Ulanet

Ludwig²,

Kahn

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

221

173

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The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. Surprisingly, preclinical trials with an inhibitory monoclonal antibody to IGF-1R did not significantly impact tumor growth, prompting us to investigate the involvement of IR. The levels of IR were found to be significantly up-regulated during multistep progression from hyperplastic lesions to islet tumors. Its functional involvement was revealed by genetic disruption of the IR gene in the oncogene-expressing pancreatic β cells, which resulted in reduced tumor burden accompanied by increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to anti–IGF-1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed resistance to IGF-1R inhibition in human breast cancer cells. The results predict that elevated IR signaling before and after treatment will respectively manifest intrinsic and adaptive resistance to anti–IGF-1R therapies.

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“…The CAFproduced HB-EGF enhanced cancer cell proliferation. There is a report that HB-EGF plays a role in tumor progression in pericytes in a mouse model of pancreatic neuroendocrine tumorigenesis (35). Therefore, HB-EGF might contribute to cancer progression by various means.…”

Section: Discussionmentioning

confidence: 99%

HB-EGF and PDGF Mediate Reciprocal Interactions of Carcinoma Cells with Cancer-Associated Fibroblasts to Support Progression of Uterine Cervical Cancers

et al. 2011

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Tumor stroma drives the growth and progression of cancers. A heparin-binding epidermal growth factor-like growth factor, HB-EGF, is an EGF receptor ligand that stimulates cell growth in an autocrine or paracrine fashion. While elevated expression of HB-EGF in cancer cells and its contribution to tumor progression are well documented, the effects of HB-EGF expression in the tumor stroma have not been clarified. Here, we show that HB-EGF is expressed in stromal fibroblasts where it promotes cancer cell proliferation. In uterine cervical cancers, HB-EGF was detected immunohistochemically in the stroma proximal to the cancer epithelium. Proliferation of cervical cancer cells in vitro was enhanced by coculture with fibroblasts isolated from tumor tissues of patients with cervical cancer. Inhibition of HB-EGF function or treatment with platelet-derived growth factor (PDGF) inhibitors abrogated cancer cell growth enhanced by cervical cancer-associated fibroblast (CCF) coculture. Furthermore, tumor formation in a mouse xenograft model was enhanced by cotransplantation of CCF or mouse embryonic fibroblasts, but not with embryonic fibroblasts from HB-EGF-deficient mice. Conversely, conditioned medium from cancer cells induced HB-EGF expression in CCF. Mechanistic investigations established that PDGF was the primary factor responsible. Together, our findings indicate that HB-EGF and PDGF reciprocally mediate the interaction of cancer cells with cancer-associated fibroblasts, promoting cancer cell proliferation in a paracrine manner that has implications for novel combinatorial cancer therapies. Cancer Res; 71(21); 6633-42. Ó2011 AACR.

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Differential Contribution to Neuroendocrine Tumorigenesis of Parallel Egfr Signaling in Cancer Cells and Pericytes

Cited by 24 publications

References 56 publications

Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis

Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis

Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy

HB-EGF and PDGF Mediate Reciprocal Interactions of Carcinoma Cells with Cancer-Associated Fibroblasts to Support Progression of Uterine Cervical Cancers

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