Cancer Resarch：RANK抑制剂化疗可有效治疗乳腺癌

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Cancer Resarch：RANK抑制剂化疗可有效治疗乳腺癌
2012-04-26
这项发表在《肿瘤杂志》上的研究表明，这种受体抑制剂可以对乳腺肿瘤有治疗效果。Bellvitge生物医学研究所（IDIBELL）的研究人员表明，RANK信号传导通路的过度激活可通过使乳腺细胞分化成干细胞的方式，促使人乳腺上皮细胞肿瘤的启动，发展和转移。这项研究的结果已在《肿瘤杂志》电子版上提出。

RANK信号传导通路

这项研究由IDIBELL转化和转移研究小组的负责人Eva Gonzalez-Suarez进行协调。一年前，该研究小组发表的一篇论文表明，这种传导通路也与小鼠模型的乳腺肿瘤有关。“我们看到，当这条途径过度活跃时，动物更容易患上乳腺癌，而当通过药物抑制这种途径后，肿瘤会消退。”（2010年，自然杂志，Gonzalez-Suarez等人）

这项研究的出发点是观察RANK的过度表达对人体的影响。首先，研究人员用健康的乳腺上皮细胞株，发现“RANK受体的过度表达出现诱导干细胞和上皮间质转化到乳腺细胞的特征，表现出恶性肿瘤特征，但不发展成肿瘤。”下一步是观察蛋白质过度表达对乳腺肿瘤细胞的的影响。“我们看到它促使肿瘤干细胞增长的过程，并且当我们将其注入动物模型中后，肿瘤的发生和转移会增加。”

最后，他们使用了乳腺肿瘤的临床标本。具有高水平RANK的肿瘤细胞与基底类型肿瘤，高级肿瘤，以及更多具有扩散和转移特点的侵略性肿瘤相联系。这意味着，“高蛋白质水平与不良的预后肿瘤相关。”因此，这项研究证实在人体细胞中同样会出现已经在老鼠身上看到的情况，“RANK信号传导通路激活的增加，可能会与乳腺癌启动的增加及其进展和转移相关联。”

临床应用

下一步，根据研究人员EvaGonzalez-Suarez的发现，“首先要通过大量的样本来确证这些研究，然后探索治疗的可能性。”如Gonzalez-Suarez的解释，“有一种理论：化疗杀死肿瘤细胞，但不影响癌症干细胞，这可能在治疗后会再次启动肿瘤。如果这种途径确实有重新启动肿瘤能力及增加肿瘤转移的能力，那么RANK抑制剂与化疗相结合可能会有重要的治疗效果。”目前，有一种RANK信号传导通路抑制剂在诊所中使用，用于治疗骨质疏松症和骨转移。

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相关文献
RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis.
Cancer Res 2012 Apr;:

Palafox M Ferrer I Pellegrini P Vila S Hernandez-Ortega S Urruticoechea A Climent F Soler MT Muñoz P Viñals F Tometsko M Branstetter D Dougall WC González-Suárez E

Cancer Epigenetics and Biology Program, IDIBELL.

Abstract
Paracrine signaling through RANK pathway mediates the expansion of mammary epithelia that occurs during pregnancy and activation of RANK pathway promotes mammary tumorigenesis in mice. In this study we extend these previous data to human cells and demonstrate that the RANK pathway promotes the development of mammary stem cells and breast cancer. Overexpression of RANK (FL-RANK) in a panel of tumoral and normal human mammary cells induces the expression of breast cancer stem and basal/stem cell markers. High levels of RANK in untransformed MCF10A cells induce changes associated with both stemness and transformation including mammary gland reconstitution, epithelial-mesenchymal transition, increased migration and anchorage independent growth. In addition, spheroids of RANK-overexpressing MCF10A cells displayed disrupted acinar formation, impaired growth arrest and polarization, and luminal filling. RANK overexpression in tumor cells with non functional BRCA1, enhances invasiveness in acinar cultures and increases tumorigenesis and metastasis in immunodeficient mice. High levels of RANK were found in human primary breast adenocarcinomas that lack expression of the hormone receptors, estrogen and progesterone, and in tumors with high pathological grade and proliferation index; high RANK/RANKL expression was significantly associated with metastatic tumors. Together, our findings demonstrate that RANK promotes tumor initiation, progression and metastasis in human mammary epithelial cells by increasing the population of CD44+CD24- cells, inducing stemness and epithelial mesenchymal transition. These results suggest that RANK expression in primary breast cancer associates with poor prognosis.