Inhibition of carcinoma cell‐derived VEGF reduces inflammatory characteristics in xenograft carcinoma

Salnikov, Alexei V.; Heldin, Nils‐Erik; Stuhr, Linda Elin Birkhaug; Wiig, Helge; Gerber, Hans‐Peter; Reed, Rolf K.; Rubin, Kristofer

doi:10.1002/ijc.22217

Cited by 56 publications

(67 citation statements)

References 51 publications

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“…Furthermore, bevacizumab significantly enhanced sensitivity to cisplatin. Bevacizumab is believed to normalize intratumoral blood vessels, which are markedly different from their counterparts in normal tissue (46). Intratumoral, neoangiogenic vessels are hyperpermeable, leading to interstitial hypertension and impaired perfusion in tumors.…”

Section: Discussionmentioning

confidence: 99%

Maintenance Treatment with Bevacizumab Prolongs Survival in anIn vivoOvarian Cancer Model

Mabuchi

Terai

Morishige

et al. 2008

Clinical Cancer Research

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Purpose: Vascular endothelial growth factor (VEGF) plays a central role in tumor angiogenesis and is regarded as a promising therapeutic target.We hypothesized that treatment with bevacizumab, a humanized recombinant anti-VEGF monoclonal antibody, could enhance antitumor response to cisplatin and prolong survival in a murine ovarian cancer model. Experimental Design: We conducted an MTS assay to examine the effect of bevacizumab on proliferation of the VEGF producing human ovarian cancer cell lines in vitro. Next, the antiangiogenic activity of bevacizumab was investigated by in vivo angiogenesis and wound healing assays.We then determined the toxicity and antitumor response of bevacizumab and cisplatin as single agents or in combination in xenograft models of ovarian cancer. Finally, using the same xenograft model, we examined the effect of these regimens, as well as bevacizumab maintenance therapy, on survival. Results: Bevacizumab had no effect on the proliferation of ovarian cancer cells in vitro but significantly inhibited angiogenesis and delayed wound healing in vivo. Bevacizumab inhibited i.p. tumor growth and ascites production in the nu/nu mouse xenograft model and enhanced the therapeutic efficacy of cisplatin. Combination therapy with bevacizumab and cisplatin for 3 weeks was associated with complete disappearance of all macroscopic evidence of disease. Moreover, maintenance treatment with bevacizumab after 3 weeks of induction combination therapy inhibited recurrence and significantly prolonged survival. Conclusions: Bevacizumab has significant antitumor activity not only as a single agent or in combination with cisplatin but may also prolong survival when used as maintenance therapy after a complete response to cisplatin-based chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Maintenance Treatment with Bevacizumab Prolongs Survival in anIn vivoOvarian Cancer Model

Mabuchi

Terai

Morishige

et al. 2008

Clinical Cancer Research

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“…The increased ECV in fibromodulin-deficient carcinomas also suggests that the collagen scaffold is less stiff, allowing tumors to swell because of the high plasma protein content in the carcinoma interstitium that results from the leaky blood vessels. Indeed, treatment of KAT-4 carcinomas with a specific inhibitor of carcinoma cell-derived vascular endothelial growth factor (Bevacizumab) decreases plasma protein leakage and reduces the ECV (19). An increased hydraulic conductivity and fluid flow in carcinomas may also explain the increased efficacy of chemotherapy in KAT-4 carcinomas pretreated with Fc:T␤RII (17).…”

Section: Discussionmentioning

confidence: 99%

“…Tortuous and leaky blood vessels, and absence of lymph drainage in tumors have also been suggested to be involved in the generation of the elevated tumor IFP. Inhibition of plasma protein leakage by interfering with vascular endothelial growth factor reduces IFP in experimental carcinomas (18,19) and human rectal carcinoma (15). Little is known, however, about how the structure and composition of the ECM in the stroma influence carcinoma IFP.…”

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confidence: 99%

Collagen-binding proteoglycan fibromodulin can determine stroma matrix structure and fluid balance in experimental carcinoma

Oldberg¹,

Kalamajski²,

Salnikov

et al. 2007

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

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Research on the biology of the tumor stroma has the potential to lead to development of more effective treatment regimes enhancing the efficacy of drug-based treatment of solid malignancies. Tumor stroma is characterized by distorted blood vessels and activated connective tissue cells producing a collagen-rich matrix, which is accompanied by elevated interstitial fluid pressure (IFP), indicating a transport barrier between tumor tissue and blood. Here, we show that the collagen-binding proteoglycan fibromodulin controls stroma structure and fluid balance in experimental carcinoma. Gene ablation or inhibition of expression by antiinflammatory agents showed that fibromodulin promoted the formation of a dense stroma and an elevated IFP. Fibromodulindeficiency did not affect vasculature but increased the extracellular fluid volume and lowered IFP. Our data suggest that fibromodulin controls stroma matrix structure that in turn modulates fluid convection inside and out of the stroma. This finding is particularly important in relation to the demonstration that targeted modulations of the fluid balance in carcinoma can increase the response to cancer therapeutic agents.physiology ͉ TGF-␤ ͉ tumor physiology ͉ inflammation ͉ interstitial fluid pressure

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“…In vitro assays have also demonstrated that CAFs induce resistance to chemotherapy via secreting cytokines (16,22,23). Besides chemotherapy agents, inhibiting CAFs may also enhance the effects of bevacizumab (rhuMab VEGF, Avastin) even in bevacizumab-resistant GC cells (24), which is similar to the selective susceptibility of α-SMA-deficient vessels to bevacizumab (25). CAFs are the primarily source of VEGF, cancer epithelial cells are able to produce VEGF and the level of VEGF is increased through the cancer-stromal interaction (26).…”

Section: Discussionmentioning

confidence: 99%

“…CAFs are the primarily source of VEGF, cancer epithelial cells are able to produce VEGF and the level of VEGF is increased through the cancer-stromal interaction (26). VEGFs and their receptors have been revealed to modulate vascular permeability activity, leading to enhanced interstitial fluid pressure in the tumor stroma, which is associated with chemotherapeutic resistance (25).…”

Section: Discussionmentioning

confidence: 99%

Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice

Wang

Jiang

et al. 2017

Oncol Lett

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Abstract. The present study aimed to evaluate whether capecitabine or 5-fluorouracil (5-Fu) chemotherapy with the metronomic pattern may cause significant chemoresistance compared with the traditional pattern, and whether CAFs are involved in drug resistance. SGC-7901 cells were subcutaneously injected into the nude mice, and the mice were divided into five groups: The control group, intraperitoneally injected with normal saline; the 5-Fu conventional dose group [5-Fu maximum tolerated dose (MTD) group], intraperitoneally injected with 50 mg/kg, twice per week for 2 weeks, with an 1-week discontinuation for 6 weeks; the capecitabine conventional dose group (capecitabine MTD group), intragastric 500 mg/kg, twice per week for 2 weeks, with a 1-week discontinuation for 6 weeks; the 5-Fu metronomic group [5-Fu low-dose metronomic (LDM) group], intraperitoneally injected with 15 mg/kg, twice a week for 6 weeks; and the capecitabine metronomic group (capecitabine LDM group), intragastric administration at 200 mg/kg, twice a week for 6 weeks. The chemotherapy resistance markers [glutathione transferase Pi (GSTP) and multidrug resistance protein 1 (MDR1)] were detected by immunohistochemical staining (IHC), and the association of the expression of these markers with the chemotherapy administration patterns was analyzed. Vascular endothelial growth factor (VEGF) and the cancer-associated fibroblast (CAF) marker α-smooth muscle actin were also examined by IHC to illustrate the possible mechanism of chemoresistance. The expression of GSTP and MDR1 in the MTD groups was significantly higher compared with those of the LDM groups (P<0.01). Furthermore, the number of CAFs and the level of VEGF in the MTD groups were significantly higher compared with those of the LDM groups (P<0.05). The low dose metronomic chemotherapy did not increase the risk of chemoresistance compared with the conventional dose traditional chemotherapy in terms of capecitabine or 5-Fu, the increasing amount of CAFs in the microenvironment of cancer cell following therapy may protect cell from capecitabine or 5-Fu via producing VEGF to increase vascularization.

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Inhibition of carcinoma cell‐derived VEGF reduces inflammatory characteristics in xenograft carcinoma

Cited by 56 publications

References 51 publications

Maintenance Treatment with Bevacizumab Prolongs Survival in anIn vivoOvarian Cancer Model

Maintenance Treatment with Bevacizumab Prolongs Survival in anIn vivoOvarian Cancer Model

Collagen-binding proteoglycan fibromodulin can determine stroma matrix structure and fluid balance in experimental carcinoma

Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice

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