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首页 » 癌症研究 » Oncotarget:肿瘤微环境如何介导癌细胞对常规化疗产生耐受性?

Oncotarget:肿瘤微环境如何介导癌细胞对常规化疗产生耐受性?

来源:生物谷 2016-09-06 23:52

图片来源:medicalxpress.com

2016年9月7日 讯 /生物谷BIOON/ --近日,刊登于国际杂志Oncotarget上的一项研究报告中,来自Bellvitge生物医学研究所的研究人员通过研究揭示了肿瘤微环境在结直肠癌对疗法产生耐受性过程中的关键作用,结直肠癌是全球第四大常见的癌症,也是引发癌症患者死亡的主要原因。文章中,研究者揭示了肿瘤微环境中特定分子如何保护肿瘤细胞免于常规化疗方法的杀灭,对疗法产生耐受性是如今很多癌症患者面临的巨大治疗障碍,因此阐明癌细胞对疗法产生耐受性的机制就显得尤为重要了。

癌相关的成纤维细胞(CAFs)是和原发性肿瘤细胞非常相近的一类正常细胞,研究者David G. Molleví表示,由CAFs分泌的特定细胞因子、炎症趋化因子及其它可溶性因子能够诱导减缓细胞循环的过程,从而影响肿瘤细胞的增殖;当在常规化疗存在的情况下,诸如上述因子就会稳定并且激活分泌的下游蛋白,从而尽可能地减少疗法的效用,然而目前有报道表明,对许多细胞因子有偏好的JAK/STAT信号通路的抑制或许就可以逆转上述过程。

肿瘤微环境作为促进癌症进展以及在耐药性产生过程中的重要一环,其重要性如今被越来越多的科学家们所认识到,研究者认为,尽管当前癌症研究主要针对开发靶向作用特殊靶点的新型疗法,但很多肿瘤依然能够利用常规的细胞毒性疗法所治疗,因此药物耐受性依然是癌症治疗是否能够成功的关键。

从临床角度来讲,鉴别出能够介导肿瘤微环境相关的药物耐受性的可溶性因子,或许就为科学家们有效克服癌细胞的耐受性提供了非常有价值的信息,而阻断合成上述可溶性因子的关键细胞的功能或许就可以避免这些分子对癌细胞产生的保护性效应,这或许就可以更好地促进肿瘤细胞对化疗方法更加敏感。(生物谷Bioon.com)

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Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells

Samuel Gonçalves-Ribeiro1, Natalia Guillen Díaz-Maroto1, Mireia Berdiel-Acer1, Antonio Soriano2, Jordi Guardiola2, Mercedes Martínez-Villacampa3, Ramon Salazar3, Gabriel Capellà4, Alberto Villanueva1, Eva Martínez-Balibrea5, David G. Molleví1

The importance of tumor microenvironment (TME) as a relevant contributor to cancer progression and its role in the development of de novo resistance to targeted therapies has become increasingly apparent. However, the mechanisms of microenvironment-mediated drug resistance for nonspecific conventional chemotherapeutic agents, such as platinum compounds or antimetabolites, are still unclear. Here we describe a mechanism induced by soluble factors released by carcinoma-associated fibroblasts (CAFs) that induce the translocation of AKT, Survivin and P38 to the nucleus of tumor cells. These changes are guided to ensure DNA repair and the correct entrance and exit from mitosis in the presence of chemotherapy. We used conditioned media (CM) from normal-colonic fibroblasts and paired CAFs to assess dose response curves of oxaliplatin and 5-fluorouracil, separately or combined, compared with standard culture medium. We also evaluated a colony-forming assay and cell death to demonstrate the protective role of CAF-CM. Immunofluorescence confirmed the translocation of AKT, P38 and Survivin to the nucleus induced by CAF-soluble factors. We also have shown that STAT3 or P38 inhibition provides a promising strategy for overcoming microenvironment-mediated resistance. Conversely, pharmacologic AKT inhibition induces an antagonistic effect that relieves a cMET and STAT3-mediated compensatory feedback that might explain the failure of AKT inhibitors in the clinic so far.

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