Transient tumor-fibroblast interactions increase tumor cell malignancy by a TGF-Beta mediated mechanism in a mouse xenograft model of breast cancer.
Transient tumor-fibroblast interactions increase tumor cell malignancy by a TGF-Beta mediated mechanism in a mouse xenograft model of breast cancer.
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在小鼠乳腺癌异种移植模型中，短暂的肿瘤-成纤维细胞相互作用通过 TGF-β 介导的机制增加了肿瘤细胞的恶性程度。
DOI：
10.1371/journal.pone.0009832
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发表时间：
2010-03-23
期刊：
影响因子：
3.7
通讯作者：
Niederhuber JE
中科院分区：
文献类型：
--
作者：
Stuelten CH;Busch JI;Tang B;Flanders KC;Oshima A;Sutton E;Karpova TS;Roberts AB;Wakefield LM;Niederhuber JE
癌是由相互相互作用的细胞组成的复杂社会，其中正常稳态机制逐渐失效，导致实质成分不适当地扩张并最终扩散到远处。当癌细胞转移时，它首先会暴露于直接肿瘤微环境中与癌症相关的成纤维细胞，然后在穿过下面的结缔组织进入血流时暴露于正常成纤维细胞。肿瘤细胞与基质成纤维细胞的相互作用通过尚未完全了解的机制影响肿瘤生物学。在这里，我们报告了正常基质成纤维细胞在侵袭性肿瘤向转移性肿瘤进展中的作用。使用人转移性乳腺癌细胞（MCF10CA1a）和正常鼠真皮成纤维细胞的共培养系统，我们发现两种细胞类型共培养（CoCM）条件的培养基增加了MCF10CA1a细胞的体外迁移和分散，而同型培养条件的培养基几乎没有影响。在体外用 CoCM 短暂处理 MCF10CA1a 细胞可加速体内原位肿瘤的生长，并导致转移性植入模式扩大。 CoCM 对 MCF10CA1a 细胞的作用依赖于肿瘤细胞影响下成纤维细胞分泌的少量活性 TGF-β1，并且需要肿瘤细胞中完整的 ALK5-、p38- 和 JNK 信号传导。总之，这些结果表明，肿瘤细胞和正常成纤维细胞之间的短暂相互作用可以改变局部微环境的无细胞成分，从而诱导致瘤性的持久增加并改变体内癌细胞的转移模式。 TGF-β 似乎是这一过程中的关键参与者，为开发针对 TGF-β 途径的抗癌疗法提供了进一步的理论依据。
Carcinoma are complex societies of mutually interacting cells in which there is a progressive failure of normal homeostatic mechanisms, causing the parenchymal component to expand inappropriately and ultimately to disseminate to distant sites. When a cancer cell metastasizes, it first will be exposed to cancer associated fibroblasts in the immediate tumor microenvironment and then to normal fibroblasts as it traverses the underlying connective tissue towards the bloodstream. The interaction of tumor cells with stromal fibroblasts influences tumor biology by mechanisms that are not yet fully understood. Here, we report a role for normal stroma fibroblasts in the progression of invasive tumors to metastatic tumors. Using a coculture system of human metastatic breast cancer cells (MCF10CA1a) and normal murine dermal fibroblasts, we found that medium conditioned by cocultures of the two cell types (CoCM) increased migration and scattering of MCF10CA1a cells in vitro, whereas medium conditioned by homotypic cultures had little effect. Transient treatment of MCF10CA1a cells with CoCM in vitro accelerated tumor growth at orthotopic sites in vivo, and resulted in an expanded pattern of metastatic engraftment. The effects of CoCM on MCF10CA1a cells were dependent on small amounts of active TGF-β1 secreted by fibroblasts under the influence of the tumor cells, and required intact ALK5-, p38-, and JNK signaling in the tumor cells. In conclusion, these results demonstrate that transient interactions between tumor cells and normal fibroblasts can modify the acellular component of the local microenvironment such that it induces long-lasting increases in tumorigenicity and alters the metastatic pattern of the cancer cells in vivo. TGF-β appears to be a key player in this process, providing further rationale for the development of anti-cancer therapeutics that target the TGF-β pathway.
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DOI：
10.1073/pnas.0401064101
发表时间：
2004-04-06
影响因子：
11.1
作者：
Kuperwasser, C;Chavarria, T;Weinberg, RA
通讯作者：
Weinberg, RA
影响因子：
64.8
作者：
Müller, A;Homey, B;Zlotnik, A
通讯作者：
Zlotnik, A
DOI：
10.1073/pnas.91.23.11236
发表时间：
1994-11-08
影响因子：
11.1
作者：
MAROULAKOU, IG;ANVER, M;GREEN, JE
通讯作者：
GREEN, JE
影响因子：
4.4
作者：
Hagemann, T;Wilson, J;Balkwill, FR
通讯作者：
Balkwill, FR
影响因子：
11.2
作者：
Ao, Mingfang;Franco, Omar E.;Hayward, Simon W.
通讯作者：
Hayward, Simon W.