Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung.
Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung.
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DOI：
10.18632/oncotarget.10327
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发表时间：
2016-12-13
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影响因子：
--
通讯作者：
Alcaraz J
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作者：
Lugo R;Gabasa M;Andriani F;Puig M;Facchinetti F;Ramírez J;Gómez-Caro A;Pastorino U;Fuster G;Almendros I;Gascón P;Davalos A;Reguart N;Roz L;Alcaraz J
癌细胞的衰老起到了抑制肿瘤的作用，而成纤维细胞则促进了肿瘤的生长。越来越多的癌症亚型中的肿瘤相关成纤维细胞(TAFs)有衰老的报道。然而，肺癌中是否存在衰老的TAFs仍不明确。我们在三种主要的组织学亚型：腺癌(ADC)、鳞癌(SCC)和大细胞癌(LCC)中检测了来自原发肺癌的TAFs和来自未受影响组织的配对对照成纤维细胞的衰老。仅在培养的LCC-TAFs中一致观察到三个独立的衰老标志物(衰老相关的β-半乳糖苷酶、永久生长停滞和铺展)，显示出选择性的早衰。有趣的是，SCC-TAFs在没有衰老标志物的情况下表现出较差的生长反应，表明是功能障碍的表型而不是衰老。正常成纤维细胞与LCC(但不是ADC或SCC)癌细胞共培养足以使成纤维细胞通过氧化应激而衰老，这表明LCC-TAFs的衰老是由异型信号驱动的。此外，与正常成纤维细胞相比，衰老成纤维细胞在培养中为LCC细胞提供了选择性生长和侵袭优势。同样，当衰老的成纤维细胞与LCC细胞共同注射到裸鼠体内时，可以促进肿瘤的生长和肿瘤细胞的肺部播散，而不是对照成纤维细胞所产生的效果。这些结果定义了肺TAFs的亚型特异性异常表型，从而挑战了肺TAFs是一个不同亚型的肌成纤维细胞样细胞群的普遍假设。重要的是，由于LCC在临床上常常因其侵袭性而与众不同，我们认为衰老的TAFs可能有助于LCC肿瘤的选择性侵袭行为。
Senescence in cancer cells acts as a tumor suppressor, whereas in fibroblasts enhances tumor growth. Senescence has been reported in tumor associated fibroblasts (TAFs) from a growing list of cancer subtypes. However, the presence of senescent TAFs in lung cancer remains undefined. We examined senescence in TAFs from primary lung cancer and paired control fibroblasts from unaffected tissue in three major histologic subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Three independent senescence markers (senescence-associated beta-galactosidase, permanent growth arrest and spreading) were consistently observed in cultured LCC-TAFs only, revealing a selective premature senescence. Intriguingly, SCC-TAFs exhibited a poor growth response in the absence of senescence markers, indicating a dysfunctional phenotype rather than senescence. Co-culturing normal fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to render fibroblasts senescent through oxidative stress, indicating that senescence in LCC-TAFs is driven by heterotypic signaling. In addition, senescent fibroblasts provided selective growth and invasive advantages to LCC cells in culture compared to normal fibroblasts. Likewise, senescent fibroblasts enhanced tumor growth and lung dissemination of tumor cells when co-injected with LCC cells in nude mice beyond the effects induced by control fibroblasts. These results define the subtype-specific aberrant phenotypes of lung TAFs, thereby challenging the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless of their subtype. Importantly, because LCC often distinguishes itself in the clinic by its aggressive nature, we argue that senescent TAFs may contribute to the selective aggressive behavior of LCC tumors.