Bevacizumab-Based Therapies in the First-Line Treatment of Metastatic Colorectal Cancer

Strickler, John H.; Hurwitz, Herbert I.

doi:10.1634/theoncologist.2012-0003

Cited by 70 publications

(49 citation statements)

References 78 publications

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“…21,22 Therefore, identification of proangiogenic genes and their products that lead to angiogenesis is critical for providing new potential therapeutic targets. In current oncological practice, the VEGF-targeted agent bevacizumab has been established as a first-line treatment for metastatic CRC, [23][24][25] suggesting especially important roles for angiogenic factors in CRC progression. Here, we showed that GPR120 signaling promoted angiogenesis by inducing secretion of proangiogenic factors VEGF, IL-8 and COX-2-derived PGE 2 in vitro and in xenograph mouse model.…”

Section: Gpr120 Is Induced In Human Crc Tissues and Its Expression Ismentioning

confidence: 99%

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

et al. 2013

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G-protein-coupled receptor 120 (GPR120) functions as a receptor for unsaturated long-chain free fatty acids and has an important role in regulating lipid and glucose metabolism. However, a role for GPR120 in the development of tumors has not yet been clarified. Here, we show that GPR120 signaling promotes angiogenic switching and motility of human colorectal carcinoma (CRC) cells. We show that the expression of GPR120 is significantly induced in CRC tissues and cell lines, which is associated with tumor progression. Activation of GPR120 signaling in human CRC promotes angiogenesis in vitro and in vivo, largely by inducing the expression and secretion of proangiogenic mediators such as vascular endothelial growth factor (VEGF), interleukin-8 and cyclooxygenase-2-derived prostaglandin E 2 . The PI3K/Akt-NF-kB pathway is activated by GPR120 signaling and is required for GPR120 signaling-induced angiogenic switching in CRC cells. And, GPR120 activation enhances the motility of CRC cells and induces epithelial-mesenchymal transition. Furthermore, in vivo study shows that activation of GPR120 promotes angiogenesis and tumor growth. Finally, we find that GPR120 expression is positively correlated with VEGF expression and inversely correlated with the epithelial marker E-cadherin in CRC tissues. Collectively, our results demonstrate that GPR120 functions as a tumor-promoting receptor in CRC and, therefore, shows promise as a new potential target for cancer therapeutics.

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Section: Gpr120 Is Induced In Human Crc Tissues and Its Expression Ismentioning

confidence: 99%

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

et al. 2013

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“…The LoVo Bev-R and control cells were respectively implanted into the left flank of 15 nude mice, and 3-BrPA was injected intraperitoneally after the xenograft volume reached 300 mm 3 . We measured tumor sizes 6 days after injection of 3-BrPA and found that the LoVo Bev-R xenografts showed very limited growth ($350 mm 3 ). On the contrary, the tumor sizes in the control group increased by over one fold (Fig.…”

Section: Glycolytic Blockade Induced Cell Senescence and Growth Supprmentioning

confidence: 99%

“…Given the pivotal role of VEGF-regulated angiogenesis in colorectal cancer progression, anti-VEGF therapeutic strategies hold promise for the treatment of advanced colorectal cancer (2). Bevacizumab, an antibody against VEGF, is currently used in first-line metastatic colorectal cancer treatment in combination with other chemotherapeutic reagents (3). However, the effectiveness of bevacizumab, especially on the overall survival of patients with metastatic colorectal cancer, has been a topic of much debate (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Colorectal Cancer Cells Refractory to Anti-VEGF Treatment Are Vulnerable to Glycolytic Blockade due to Persistent Impairment of Mitochondria

Wang

et al. 2013

Molecular Cancer Therapeutics

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Antiangiogenesis therapy has shed new light on cancer treatment, but its effectiveness, especially for overall patient survival, is still controversial. Here, we show that antiangiogenesis treatment causes a persistent suppression of mitochondria biogenesis in colorectal cancer cells, which renders them more sensitive to glycolytic blockade therapy. We first analyzed bevacizumab-resistant colon cancer xenografts by twodimensional Blue Native/SDS-PAGE and found a serious and persistent loss of mitochondrial protein complex I. Further metabolic assays revealed significantly impaired mitochondrial function and hyperactive glycolysis, which were concomitant with the upregulation of HIF-1 and Hsp70. The treatment of bevacizumab-resistant cells with the glycolysis inhibitor 3-BrPA caused cell senescence in vitro. Intraperitoneal injection of 3-BrPA to xenograft mice bearing bevacizumab-resistant cells also resulted in smaller tumor volume and longer survival. These data provide direct evidence for the mitochondrial destruction of bevacizumab-resistant tumor cells and suggest that glycolysis blockade may potentiate the therapeutic effect of antiangiogenesis treatment.

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“…Combining chemotherapy with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab may further improve outcome in the advanced disease setting [2]. Clinical trials conducted on mCRC patients demonstrated higher activity and efficacy for LOHP- or CPT-11-based doublets with biologics, with response rates (RRs) around 40-50% and a median OS around 24 months [3]. …”

Section: Introductionmentioning

confidence: 99%

<b><i>Topoisomerase 1</i></b> Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients

et al. 2016

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Objective:Topoisomerase 1 (topo-1) is an important target for the treatment of metastatic colorectal cancer (CRC). The aim of the present study was to evaluate the correlation between topo-1 single-nucleotide polymorphisms (SNPs) and clinical outcome in metastatic CRC (mCRC) patients. Methods: With the use of specific software (PROMO 3.0), we performed an in silico analysis of topo-1 promoter SNPs; the rs6072249 and rs34282819 SNPs were included in the study. DNA was extracted from 105 mCRC patients treated with FOLFIRI ± bevacizumab in the first line. SNP genotyping was performed by real-time PCR. Genotypes were correlated with clinical parameters (objective response rate, progression-free survival, and overall survival). Results: No single genotype was significantly associated with clinical variables. The G allelic variant of rs6072249 topo-1 SNP is responsible for GC factor and X-box-binding protein transcription factor binding. The same allelic variant showed a nonsignificant trend toward a shorter progression-free survival (GG, 7.5 months; other genotypes, 9.3 months; HR 1.823, 95% CI 0.8904-3.734; p = 0.1). Conclusion: Further analyses are needed to confirm that the topo-1 SNP rs6072249 and transcription factor interaction could be a part of tools to predict clinical outcome in mCRC patients treated with irinotecan-based regimens.

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Bevacizumab-Based Therapies in the First-Line Treatment of Metastatic Colorectal Cancer

Cited by 70 publications

References 78 publications

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

Colorectal Cancer Cells Refractory to Anti-VEGF Treatment Are Vulnerable to Glycolytic Blockade due to Persistent Impairment of Mitochondria

<b><i>Topoisomerase 1</i></b> Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients

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