Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front
Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front
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DOI：
10.1158/0008-5472.can-05-1231
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发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Rio, MC
中科院分区：
文献类型：
--
作者：
Andarawewa, KL;Motrescu, ER;Rio, MC
癌症发展过程中最初的侵袭过程在很大程度上仍不清楚。基质分解素-3/基质金属蛋白酶11(ST3/MMPII)与肿瘤侵袭和预后不良有关。我们提出了新的证据，表明存在于人类乳腺肿瘤侵袭前沿的脂肪细胞是由癌细胞诱导表达ST3的。利用小鼠同基因模型，光镜和电子显微镜显示，在ST3基因缺陷小鼠中，而在野生型小鼠中，强迫癌细胞-脂肪细胞相互作用/串扰导致脂肪细胞膜改变，允许癌细胞脂肪渗透和死亡。因此，脂肪细胞参与了癌细胞最初进入结缔组织的存活过程，这种作用是ST3介导的。这提示ST3可能在脂肪细胞代谢中发挥作用。相应地，ST3基因缺陷小鼠表现出脂肪过剩和过氧化体增殖物激活受体γ(PPARγ)和脂肪细胞蛋白2(AP2)成脂标志物的mRNA水平增加，表明在体内，ST3负向调节脂肪稳态。此外，随着PPARγ和aP2表达的增加，ST3缺陷的小鼠胚胎成纤维细胞分化为脂肪细胞的能力显著增强，重组ST3治疗逆转了它们的分化。因此，在体外，ST3以自分泌的方式减少脂肪细胞的分化。高成纤维细胞/脂肪细胞比率是间质的特征，瘤周成纤维细胞来源仍有争议。我们的结果支持这一观点，即侵袭性癌细胞异常地将负的ST3成脂功能恢复到近端脂肪细胞/前脂肪细胞，导致特定的瘤周成纤维细胞亚群的聚集/维持。因此，在人类乳腺肿瘤中，我们观察到表达ST3的瘤周成纤维细胞不同于表达α-平滑肌肌动蛋白的肌成纤维细胞。这构成了在结缔组织侵袭的早期阶段，基质金属蛋白酶在癌细胞-脂肪细胞相互作用/串扰中的意义的第一个报道。
The initial invasive processes during cancer development remain largely unknown. Stromelysin-3/matrix metalloproteinase 11 (ST3/MMPII) is associated with tumor invasion and poor prognosis. We present novel evidence that adipocytes present at human breast tumor invasive front are induced by cancer cells to express ST3. Using mouse syngeneic model, light and electron microscopy showed that in ST3-deficient mice but not in wild-type mice, forced cancer cell-adipocyte interaction/crosstalk results in adipocyte membrane alteration, allowing cancer cell fat infiltration and death. Thus, adipocytes are involved in initial cancer cell survival into connective tissue, and this effect is ST3 mediated. This suggested that ST3 might play a role in adipocyte metabolism. Accordingly, ST3-deficient mice exhibited fat excess and increased mRNA levels of peroxisome proliferator-activated receptor gamma (PPAR gamma) and adipocyte protein 2 (aP2) adipogenic markers, indicating that, in vivo, ST3 negatively regulates fat homeostasis. Moreover, ST3-deficient mouse embryonic fibroblasts exhibited a dramatic enhanced potential to differentiate into adipocytes associated with increased PPAR gamma and aP2 expression, and recombinant ST3 treatment reverted their differentiation. Thus, in vitro, ST3 reduces adipocyte differentiation in an autocrine manner. High fibroblasts/adipocytes ratio is a stroma feature, and peritumoral fibroblast origin remains debated. Our results support the concept that invading cancer cells aberrantly restore the negative ST3 function on adipogenesis into proximal adipocytes/preadipocytes, leading to the accumulation/maintenance of a particular peritumoral fibroblast subpopulation. Accordingly, in human breast tumors, we observed that ST3-expressing peritumoral fibroblasts are distinct from alpha-smooth muscle actin-expressing myofibroblasts. This constitutes the first report of implication of a MMP in cancer cell-adipocyte interaction/ crosstalk during early steps of connective tissue invasion.