Connective tissue growth factor–specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer

Aikawa, Takuma; Gunn, Jason R.; Spong, Suzanne; Klaus, Stephen J.; Korc, Murray

doi:10.1158/1535-7163.mct-05-0516

Cited by 143 publications

(120 citation statements)

References 55 publications

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“…Although CTGF antagonism would be hypothesized to disrupt the fibrotic architecture of PDA tumors, we instead found that FG-3019 treatment left the stromal content grossly intact. Also, in contrast to previous xenograft results with FG-3019 that demonstrated antitumor activity (41,42), treatment with FG-3019 alone did not result in significant antitumoral responses in KPC mice. Previous reports have also described CTGF as a critical mediator of vascular remodeling by regulating pericyte function and endothelial basement membrane formation during angiogenesis (43).…”

Section: Discussioncontrasting

confidence: 99%

“…Previous reports have also described CTGF as a critical mediator of vascular remodeling by regulating pericyte function and endothelial basement membrane formation during angiogenesis (43). In the tumor microenvironment, CTGF and the CXCR2 chemokine ligand axis have also been implicated as promoters of tumor angiogenesis in a variety of PDA models (42,44). In contrast to the prior finding that inhibition of CXCR2 resulted in reduced CTGF levels and regulated blood vessel density and tumor growth in the related Ptf1a cre/+ ;LSL-Kras G12D/+ ;Tgfbr2 flox/flox mouse model (44), FG-3019 had no effect on mean vessel density over the time course of treatment in KPC mice, and suggests that the relevant therapeutic targets here are neoplastic cell-intrinsic.…”

Section: Discussionmentioning

confidence: 98%

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CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Neeße

Frese

Bapiro

et al. 2013

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

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214

173

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Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant desmoplasia and poor tissue perfusion. These features are proposed to limit the access of therapies to neoplastic cells and blunt treatment efficacy. Indeed, several agents that target the PDA tumor microenvironment promote concomitant chemotherapy delivery and increased antineoplastic response in murine models of PDA. Prior studies could not determine whether chemotherapy delivery or microenvironment modulation per se were the dominant features in treatment response, and such information could guide the optimal translation of these preclinical findings to patients. To distinguish between these possibilities, we used a chemical inhibitor of cytidine deaminase to stabilize and thereby artificially elevate gemcitabine levels in murine PDA tumors without disrupting the tumor microenvironment. Additionally, we used the FG-3019 monoclonal antibody (mAb) that is directed against the pleiotropic matricellular signaling protein connective tissue growth factor (CTGF/CCN2). Inhibition of cytidine deaminase raised the levels of activated gemcitabine within PDA tumors without stimulating neoplastic cell killing or decreasing the growth of tumors, whereas FG-3019 increased PDA cell killing and led to a dramatic tumor response without altering gemcitabine delivery. The response to FG-3019 correlated with the decreased expression of a previously described promoter of PDA chemotherapy resistance, the X-linked inhibitor of apoptosis protein. Therefore, alterations in survival cues following targeting of tumor microenvironmental factors may play an important role in treatment responses in animal models, and by extension in PDA patients.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 98%

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Neeße

Frese

Bapiro

et al. 2013

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

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214

173

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“…Loss of CCN2 expression in embryonic mesenchymal cells results in diminished cell migration and adhesion, and reduction in pro-angiogenic and profibrotic gene expression (Chen et al 2004;Kennedy et al 2007). Previous studies have shown that application of an antibody specific to CCN2 resulted in decreased tumour volume, metastasis and angiogenesis (Aikawa et al 2006). CCN2 expression is controlled primarily at the transcriptional level; therefore elements in its promoter are likely to contribute to its overexpression in pancreatic cancer (Blom et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Analysis of CCN2 promoter activity in PANC-1 cells: regulation by ras/MEK/ERK

Pickles

Leask

2007

J. Cell Commun. Signal.

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Connective tissue growth factor (CTGF, CCN2) is overexpressed in pancreatic cancer. We mapped the minimal CCN2 promoter active in PANC-1 cells, a human pancreatic cancer cell line. Within this region, Sp1, BCE-1 and Ets elements were important for the activity of the CCN2 promoter. Constitutive hyperactivated ras is a hallmark of cancers, including that of the pancreas. Treatment of PANC-1 cells with the MEK inhibitor U0126 or the Sp1 inhibitor mithramycin reduced CCN2 mRNA and promoter activity. Mutation of the BCE-1, but not Sp1 or Ets, site abolished the responsiveness of the CCN2 promoter to U0126. Overexpressing constitutively active MEK1 or ras activated CCN2 promoter activity. Thus CCN2 is likely to act downstream of ras in PANC-1 cells. CCN2 is overexpressed in cancer cells. Activated ras/MEK/ERK is a hallmark of cancer, and we have shown that the elevated CCN2 expression in pancreatic cancer cells is dependent on this pathway.

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“…12 CTGF may play a role as a secreted tumor suppressor protein 13 or contribute to promote tumor cell growth and invasion. 14 Some studies suggested that CTGF could also be involved in the inflammatory response. CTGF is a chemotactic factor for monocytes 15 and regulates cellular adhesion and migration in mesangial cells.…”

mentioning

confidence: 99%

CTGF Promotes Inflammatory Cell Infiltration of the Renal Interstitium by Activating NF-κB

Sánchez-López¹,

Rayego²,

Rodrigues‐Díez³

et al. 2009

Journal of the American Society of Nephrology

118

100

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Connective tissue growth factor (CTGF) is an important profibrotic factor in kidney diseases. Blockade of endogenous CTGF ameliorates experimental renal damage and inhibits synthesis of extracellular matrix in cultured renal cells. CTGF regulates several cellular responses, including adhesion, migration, proliferation, and synthesis of proinflammatory factors. Here, we investigated whether CTGF participates in the inflammatory process in the kidney by evaluating the nuclear factor-kappa B (NF-B) pathway, a key signaling system that controls inflammation and immune responses. Systemic administration of CTGF to mice for 24 h induced marked infiltration of inflammatory cells in the renal interstitium (T lymphocytes and monocytes/macrophages) and led to elevated renal NF-B activity. Administration of CTGF increased renal expression of chemokines (MCP-1 and RANTES) and cytokines (INF-␥, IL-6, and IL-4) that recruit immune cells and promote inflammation. Treatment with a NF-B inhibitor, parthenolide, inhibited CTGF-induced renal inflammatory responses, including the up-regulation of chemokines and cytokines. In cultured murine tubuloepithelial cells, CTGF rapidly activated the NF-B pathway and the cascade of mitogen-activated protein kinases, demonstrating crosstalk between these signaling pathways. CTGF, via mitogen-activated protein kinase and NF-B activation, increased proinflammatory gene expression. These data show that in addition to its profibrotic properties, CTGF contributes to the recruitment of inflammatory cells in the kidney by activating the NF-B pathway.

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Connective tissue growth factor–specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer

Cited by 143 publications

References 55 publications

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Analysis of CCN2 promoter activity in PANC-1 cells: regulation by ras/MEK/ERK

CTGF Promotes Inflammatory Cell Infiltration of the Renal Interstitium by Activating NF-κB

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