Tumor–stroma interactions reduce the efficacy of adenoviral therapy through the HGF‐MET pathway
Tumor–stroma interactions reduce the efficacy of adenoviral therapy through the HGF‐MET pathway
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DOI：
10.1111/j.1349-7006.2010.01783.x
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发表时间：
2011-02
期刊：
影响因子：
5.7
通讯作者：
T. Yasui;K. Ohuchida;Ming Zhao;M. Onimaru;Takuya Egami;H. Fujita;T. Ohtsuka;K. Mizumoto;Masao Tanaka
中科院分区：
文献类型：
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作者：
T. Yasui;K. Ohuchida;Ming Zhao;M. Onimaru;Takuya Egami;H. Fujita;T. Ohtsuka;K. Mizumoto;Masao Tanaka
许多临床前研究已经显示了以腺病毒为基础的癌症基因治疗的潜力。然而，这些有希望的结果还没有成功地转化为临床。胰腺导管腺癌(PDAC)以丰富的促结缔组织间质为特征，肿瘤-间质细胞的相互作用在肿瘤的发展中起着至关重要的作用。因此，我们假设肿瘤-间质的相互作用降低了腺病毒治疗的疗效。我们利用含或不含成纤维细胞条件培养上清的Suit-2和Panc-1胰腺癌细胞，然后感染Ad-LacZ，研究成纤维细胞对腺病毒基因治疗的影响。48h后进行β-半乳糖苷酶染色。结果显示，经成纤维细胞培养上清培养后，β-半乳糖苷酶阳性细胞数明显减少(P<；0.05)。由于肝细胞生长因子(HGF)/MET途径在肿瘤-间质相互作用中起重要作用，我们接下来研究了该途径在肿瘤-间质相互作用中的作用，从而降低了腺病毒治疗的疗效。用含或不含MET抑制剂SU11274和/或成纤维细胞条件培养上清的方法培养Suit-2细胞，然后用Ad-GFP感染。48h后计数GFP阳性细胞数。含成纤维细胞培养上清液+SU11274的GFP阳性细胞数显著多于不含SU11274的培养物。总之，我们的结果表明，PDAC中的间质细胞通过涉及HGF/MET途径的机制来减低腺病毒治疗的效果。控制这种肿瘤-间质的相互作用可能会改进PDAC的腺病毒基因治疗。(《癌症科学》2011；102：484-491)
Many preclinical studies have shown the potential of adenovirus‐based cancer gene therapy. However, successful translation of these promising results into the clinic has not yet been achieved. Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant desmoplastic stroma, and tumor–stromal cell interactions play a critical role in tumor progression. Therefore, we hypothesized that tumor–stroma interactions reduce the efficacy of adenoviral therapy. We investigated the effect of fibroblasts on adenovirus‐based gene therapy using SUIT‐2 and PANC‐1 pancreatic cancer cells cultured with or without fibroblast‐conditioned culture supernatant then infected with Ad‐LacZ. After 48 h, the cells were stained for β‐galactosidase. The results showed that the number of β‐galactosidase‐positive cells was significantly reduced after culture with fibroblast‐conditioned supernatant (P < 0.05). Because the hepatocyte growth factor (HGF)/MET pathway plays an important role in tumor–stroma interactions we next investigated the involvement of this pathway in tumor–stroma interactions leading to the decreased efficacy of adenoviral therapy. SUIT‐2 cells were cultured with or without SU11274 (a MET inhibitor) and/or fibroblast‐conditioned culture supernatant, then infected with Ad‐GFP. After 48 h, GFP‐positive cells were counted. The number of GFP‐positive cells in cultures containing fibroblast‐conditioned supernatant plus SU11274 was significantly greater than in cultures without SU11274. In conclusion, our results suggest that stromal cells in PDAC reduce the efficacy of adenoviral therapy through a mechanism involving the HGF/MET pathway. Control of such tumor–stroma interactions may lead to improvements in adenoviral gene therapy for PDAC. (Cancer Sci 2011; 102: 484–491)