Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication.
Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication.
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DOI：
10.1186/1476-4598-13-102
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发表时间：
2014-05-05
期刊：
影响因子：
37.3
通讯作者：
Kitagawa Y
中科院分区：
文献类型：
--
作者：
Hoshino Y;Hayashida T;Hirata A;Takahashi H;Chiba N;Ohmura M;Wakui M;Jinno H;Hasegawa H;Maheswaran S;Suematsu M;Kitagawa Y
同源异型盒B 9（HOXB 9）是一种转录因子，调节发育过程和肿瘤的进展，近年来被认为是与血管生成相关的重要转录因子之一。本研究旨在探讨HOXB 9在肿瘤发生和血管生成中的作用。我们使用qPCR和原位杂交检测了HOXB 9在结直肠癌中的表达。我们还使用增殖测定、ELISA、多重测定和异种移植模型检查了HOXB 9过表达在结直肠癌中的作用。在切除标本中统计学评估HOXB 9的临床意义。HOXB 9在结直肠癌标本中表达。HOXB 9在体外诱导血管生成和肿瘤增殖，这导致体内高致瘤性和较差的总体存活率。贝伐珠单抗是一种抗血管内皮生长因子（VEGF）抗体，通过抑制HOXB 9过表达异种移植物中的血管生成，显著抑制肿瘤增殖，并改善HOXB 9过表达患者的总生存期，延长无进展生存期。与人血管内皮细胞和成纤维细胞共培养的癌细胞上清液的综合多重测定表明，白细胞介素-6（IL-6）水平显着高于单培养细胞上清液中的水平。临床标本中HOXB 9过表达与IL 6表达增加显著相关。IL 6中和抗体抑制VEGF分泌和肿瘤增殖的共培养系统。HOXB 9促进血管生成因子（包括VEGF）的分泌，以通过细胞因子（包括IL 6信号传导）的微环境产生来诱导肿瘤增殖。此外，VEGF或IL 6的沉默终止肿瘤微环境中的细胞因子释放。因此，HOXB 9和IL 6可能是贝伐单抗治疗的潜在生物标志物。
Homeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis. This study aimed to investigate the role of HOXB9 in tumorigenesis and angiogenesis. We examined the expression of HOXB9 in colorectal cancer using qPCR and in situ hybridization. We also examined the effect of HOXB9 overexpression in colorectal cancer using a proliferation assay, ELISA, a multiplex assay, and xenograft models. The clinical significance of HOXB9 was statistically evaluated in resected specimens. HOXB9 was expressed in colorectal cancer specimens. HOXB9 induced angiogenesis and tumor proliferation in vitro, which resulted in high tumorigenicity in vivo and poor overall survival. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, remarkably suppressed tumor proliferation by inhibiting angiogenesis in HOXB9-overexpressing xenografts, and it improved overall survival and provided prolonged progression-free survival in HOXB9-overexpressing patients. A comprehensive multiplex assay of the supernatant of cancer cells co-cultured with human vascular endothelial cells and fibroblasts indicated significantly higher interleukin-6 (IL6) levels than those in the supernatant of monocultured cells. HOXB9 overexpression in clinical specimens was significantly correlated with increased IL6 expression. An IL6-neutralizing antibody inhibited VEGF secretion and tumor proliferation in the co-culture system. HOXB9 promotes the secretion of angiogenic factors, including VEGF, to induce tumor proliferation through microenvironmental production of cytokines including IL6 signaling. Moreover, silencing of VEGF or IL6 terminates cytokine release in tumor microenvironment. Thus, HOXB9 and IL6 may be potential biomarkers for bevacizumab treatment.
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影响因子：
3.8
作者：
NOVICK, D;SHULMAN, LM;REVEL, M
通讯作者：
REVEL, M
影响因子：
82.9
作者：
Willett, CG;Boucher, Y;Jain, RK
通讯作者：
Jain, RK
DOI：
10.1158/1078-0432.ccr-09-0731
发表时间：
2009-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
O'Connor JP;Carano RA;Clamp AR;Ross J;Ho CC;Jackson A;Parker GJ;Rose CJ;Peale FV;Friesenhahn M;Mitchell CL;Watson Y;Roberts C;Hope L;Cheung S;Reslan HB;Go MA;Pacheco GJ;Wu X;Cao TC;Ross S;Buonaccorsi GA;Davies K;Hasan J;Thornton P;del Puerto O;Ferrara N;van Bruggen N;Jayson GC
通讯作者：
Jayson GC
影响因子：
45.3
作者：
Venook, Alan P.;Niedzwiecki, Donna;Bertagnolli, Monica M.
通讯作者：
Bertagnolli, Monica M.
影响因子：
2.7
作者：
Taylor, HS
通讯作者：
Taylor, HS