Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy.
Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy.
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DOI：
10.1158/1078-0432.ccr-11-1877
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发表时间：
2012-06-01
期刊：
影响因子：
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通讯作者：
Harris AL
中科院分区：
文献类型：
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作者：
McIntyre A;Patiar S;Wigfield S;Li JL;Ledaki I;Turley H;Leek R;Snell C;Gatter K;Sly WS;Vaughan-Jones RD;Swietach P;Harris AL
贝伐单抗是一种抗VEGFA抗体，可抑制肿瘤血管系统的发育，但耐药性很常见。抗血管生成治疗诱导缺氧，我们观察到缺氧调节基因的表达增加，包括碳酸酐酶IX（CAIX），在异种移植物中对贝伐单抗治疗的反应。CAIX表达与大多数肿瘤类型的不良预后相关，并且与贝伐珠单抗治疗的转移性结直肠癌患者、恶性星形细胞瘤和复发性恶性胶质瘤的不良结局相关。我们通过shRNA敲低了结肠癌（HT29）和胶质母细胞瘤（U87）细胞系中CAIX的表达，这些细胞系具有高的CAIX缺氧诱导，并且在具有低CAIX的HCT 116细胞中过表达CAIX。我们研究了在3D培养和体内对生长速率的影响，并检查了CAIX敲减与贝伐单抗组合的影响。CAIX表达与球体和体内生长速率增加相关。令人惊讶的是，CAIX表达与体内和体外增加的坏死和凋亡相关。我们发现，酸性抑制CAIX活性超过肿瘤中发现的pH范围（pK=6.84），这可能是过量的酸自我限制细胞外酸积累的机制。另一种缺氧诱导型CA亚型CAXII的表达在3D而非2D培养中响应于CAIX敲低而上调。CAIX敲低增强了贝伐单抗治疗的效果，降低了体内肿瘤生长速率。这项工作提供了证据表明，抑制缺氧适应抗血管生成治疗增强了贝伐单抗治疗，并强调了开发抑制CAIX的小分子或抗体用于联合治疗的价值。
Bevacizumab, an anti-VEGFA antibody, inhibits the developing vasculature of tumours, but resistance is common. Antiangiogenic therapy induces hypoxia and we observed increased expression of hypoxia-regulated genes, including carbonic anhydrase IX (CAIX), in response to Bevacizumab treatment in xenografts. CAIX expression correlates with poor prognosis in most tumour types and with worse outcome in Bevacizumab-treated metastatic colorectal cancer patients, malignant astrocytoma and recurrent malignant glioma. We knocked-down CAIX expression by shRNA in a colon cancer (HT29) and a glioblastoma (U87) cell line which have high hypoxic-induction of CAIX, and over-expressed CAIX in HCT116 cells which has low CAIX. We investigated the effect on growth rate in 3D culture and in vivo, and examined the effect of CAIX knockdown in combination with Bevacizumab. CAIX expression was associated with increased growth rate in spheroids and in vivo. Surprisingly, CAIX expression was associated with increased necrosis and apoptosis in vivo and in vitro. We found that acidity inhibits CAIX activity over the pH range found in tumours (pK=6.84), and this may be the mechanism whereby excess acid self-limits the build-up of extracellular acid. Expression of another hypoxia inducible CA isoform, CAXII, was upregulated in 3D but not 2D culture in response to CAIX knockdown. CAIX knockdown enhanced the effect of Bevacizumab treatment, reducing tumour growth rate in vivo. This work provides evidence that inhibition of the hypoxic adaptation to anti-angiogenic therapy enhances Bevacizumab treatment and highlights the value of developing small molecules or antibodies which inhibit CAIX for combination therapy.