Pericytes limit tumor cell metastasis

Xian, Xiaojie

doi:10.1172/jci25705

Cited by 302 publications

(241 citation statements)

References 46 publications

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“…Moreover, clusters of fibroblast-like, asmooth muscle actin and desmin-positive cells dissociated from vessel walls were regularly observed in WT, but not in BbKO tumors (Figure 3c). These structures are symptomatic of vessel wall destabilization, and have been associated with reduced neural cell adhesion molecule (NCAM) expression by the tumor cells and metastasis (Xian et al, 2006). Deposition of collagen type I, a prominent component of the RIP1Tag2 tumor stroma (Sugimoto et al, 2006), could be observed in WT, but not BbKO tumors (Figure 3c, bottom).…”

Section: Resultsmentioning

confidence: 99%

B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic β-cell carcinogenesis

et al. 2008

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Activation of the Raf/MEK/ERK pathway, often by gainof-function mutations of RAS or RAF, is observed in many human cancers. The extracellular signal-regulated kinase (ERK) pathway is required for the proliferation of cancer cell lines harboring activating BRAF or, to a lesser extent, activating RAS mutations. It is still unclear, however, whether the pathway is required in vivo for tumor development, particularly in tumors in which B-Raf is not mutationally activated. During embryonic development, B-Raf is essential for angiogenesis in the placenta. To address the question of whether B-Raf contributed to tumor angiogenesis in vivo we conditionally ablated B-Raf in a model of pancreatic islet carcinoma driven by the functional inactivation of tumor suppressors (RIP1Tag2), which critically depends on angiogenesis for growth. We find that B-Raf is dispensable for the proliferation of tumor cells in culture, but necessary for ERK activation and for the expression of angiogenic factors by tumor cells in vivo and in vitro. In vivo, these defects result in the formation of hollow tumors with decreased vessel density and strongly reduced proliferation. The progression from adenoma to carcinoma is also significantly impaired. Thus, endogenous B-Raf contributes to the development of RIP1Tag2 tumors by supporting the stromal response and tumor progression.

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Section: Resultsmentioning

confidence: 99%

B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic β-cell carcinogenesis

et al. 2008

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“…Several Vegf antagonists have been approved by the US Food and Drug Administration 137 that increase survival in patients with metastatic breast cancer 138 and metastatic colorectal cancer 139 when combined with chemotherapy. The translational promise of this first targeted therapy against the tumour microenvironment, however, is somewhat tempered by emerging instances of resistance to anti-angiogenic therapy 140 , and examples of stromal cell targeting in animal models that unexpectedly resulted in increased invasion 48 or metastasis 141 . These data reinforce the importance of fully understanding the intricacy of cellular interactions in the tumour microenvironment, using approaches discussed in this Review, in order to isolate the cancer cells from their multiple support networks and effectively destroy them.…”

Section: Discussionmentioning

confidence: 99%

“…These examples indicate that it will be important to inhibit mobilized BMDCs alongside drugs that target cancer cells, and this synergy may in fact explain some of the therapeutic efficacy observed in certain combination trials in mice and humans to date. 141 . These data reinforce the importance of fully understanding the intricacy of cellular interactions in the tumour microenvironment, using approaches discussed in this Review, in order to isolate the cancer cells from their multiple support networks and effectively destroy them.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Microenvironmental regulation of metastasis

2008

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Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves ratelimiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.A variety of stromal cells in the surrounding environment are recruited to tumours, and these not only enhance growth of the primary cancer but also facilitate its metastatic dissemination to distant organs. Cancer cells in an aggressive primary mass are adept at exploiting that particular tissue microenvironment; however, once they leave these favourable surroundings, they must possess traits that will allow them to survive in new environments. In order for a metastasis to occur, the intravasated cancer cell must survive in the circulation, arrive at the target organ (seeding), extravasate into the parenchyma and show persistent growth 1 . Each of these stages is inefficient and some are rate limiting 1,2 . For example, senescence or apoptosis of cancer cells at the stage of entry into the metastatic site prevents the spread of the majority of circulating cells [2][3][4] . Seeding can occur to multiple organs, but metastatic tumours may grow in only one or a few 5 . There is also increasing evidence that in some cases cancer cells can lie dormant for many years, and that seeding may occur several years before diagnosis of the primary tumour [6][7][8][9][10] . In another phenomenon, termed angiogenic dormancy, there is a balance of proliferation and apoptosis that results in micrometastases that do not progress further 11,12 . The microenvironment clearly suppresses NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the malignancy of these potentially metastatic cells 10 , and their re-activation to form a clinically relevant metastasis probably occurs through perturbations in the microenvironment. Nevertheless, despite this evidence for early seeding and dormancy, tumour size and grade are the main predictors of metastasis, and this has been reinforced in recent studies in mouse models 13 and by gene expression analysis that linked large tumour size with metastasis-enhancing gene signatures 14 . It has been hypothesized that this may be due to metastatic re-seeding to primary tumours 15 . If this is the case, nothing is currently known about the underlying mechanisms. Successful metastatic outgrowth thus depends on the cumulative ability of cancer cells to appropriate distinct microenvironments at each step in the metastatic cascade: the primary tumour, systemic circulation and the final metastatic site. In this Review we discuss instruct...

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“…As discussed below, many studies testing the effects of antiangiogenic drugs have shown a presence of a "normalization window"-a time period beginning with the appearance of a normalized vascular phenotype (typically within 1 -2 days of starting treatment), and ending when features of normalization are lost Winkler et al 2004;Jain 2005b;Batchelor et al 2007;Kamoun et al 2009 Xian et al 2006;McCarty et al 2007;Mazzone et al 2009. c This is controversial given recent reports of increased metastasis after antiangiogenic therapy in certain animal models (Ebos et al 2009;Paez-Ribes et al 2009 Gorski et al 1999;Hansen-Algenstaedt et al 2000;Lee et al 2000;Kozin et al 2001;Ader et al 2003;Winkler et al 2004;Ansiaux et al 2005Ansiaux et al , 2006Pore et al 2006a;Dings et al 2007;Kashiwagi et al 2008;Batra et al 2009;Cerniglia et al 2009;Tsukada et al 2009;McGee et al 2010. g Teicher et al 1995a,b;Wildiers et al 2003;Segers et al 2006;Dickson et al 2007a,b,c;Bhattacharya et al 2008Bhattacharya et al , 2009Zhou et al 2008;Juan et al 2009;Zhou and Gallo 2009;J Liu, S Liao, B Diop-Frimpong, et al, unpubl. data. section, we discuss the key molecules implicated in tumor vessel biology with a focus on their role in regulating vascular normalization.…”

Section: Evidence For Vascular Normalization In Tumors Preclinical Evmentioning

confidence: 99%

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

Goel

Wong

Jain

2011

Cold Spring Harbor Perspectives in Medicine

294

267

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Pathological angiogenesis-driven by an imbalance of pro-and antiangiogenic signaling-is a hallmark of many diseases, both malignant and benign. Unlike in the healthy adult in which angiogenesis is tightly regulated, such diseases are characterized by uncontrolled new vessel formation, resulting in a microvascular network characterized by vessel immaturity, with profound structural and functional abnormalities. The consequence of these abnormalities is further modification of the microenvironment, often serving to fuel disease progression and attenuate response to conventional therapies. In this article, we present the "vascular normalization" hypothesis, which states that antiangiogenic therapy, by restoring the balance between pro-and antiangiogenic signaling, can induce a more structurally and functionally normal vasculature in a variety of diseases. We present the preclinical and clinical evidence supporting this concept and discuss how it has contributed to successful treatment of both solid tumors and several benign conditions.

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Pericytes limit tumor cell metastasis

Cited by 302 publications

References 46 publications

B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic β-cell carcinogenesis

B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic β-cell carcinogenesis

Microenvironmental regulation of metastasis

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

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