Peña Christopher G, Nakada Yuji, Saatcioglu Hatice D, Aloisio Gina M, Cuevas Ileana, Zhang Song, Miller David S, Lea Jayanthi S, Wong Kwok-Kin, DeBerardinis Ralph J, Amelio Antonio L, Brekken Rolf A, Castrillon Diego H
J Clin Invest. 2015 Nov 2;125(11):4063-76. doi: 10.1172/JCI82152. Epub 2015 Sep 28.
Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy in women. For most patients in whom the disease is confined to the uterus, treatment results in successful remission; however, there are no curative treatments for tumors that have progressed beyond the uterus. The serine/threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer, but the biological modes of action of LKB1 in this context remain incompletely understood. Here, we have shown that LKB1 suppresses tumor progression by altering gene expression in the tumor microenvironment. We determined that LKB1 inactivation results in abnormal, cell-autonomous production of the inflammatory cytokine chemokine (C-C motif) ligand 2 (CCL2) within tumors, which leads to increased recruitment of macrophages with prominent tumor-promoting activities. Inactivation of Ccl2 in an Lkb1-driven mouse model of endometrial cancer slowed tumor progression and increased survival. In human primary endometrial cancers, loss of LKB1 protein was strongly associated with increased CCL2 expression by tumor cells as well as increased macrophage density in the tumor microenvironment. These data demonstrate that CCL2 is a potent effector of LKB1 loss in endometrial cancer, creating potential avenues for therapeutic opportunities.
子宫内膜癌是最常见的妇科恶性肿瘤，也是女性第四大常见恶性肿瘤。对于大多数疾病局限于子宫的患者，治疗可成功实现缓解；然而，对于已进展至子宫外的肿瘤，尚无治愈性治疗方法。丝氨酸/苏氨酸激酶LKB1已被确定为子宫癌的强效抑制因子，但LKB1在这种情况下的生物学作用模式仍未完全明确。在此，我们表明LKB1通过改变肿瘤微环境中的基因表达来抑制肿瘤进展。我们确定LKB1失活会导致肿瘤内炎症细胞因子趋化因子（C-C基序）配体2（CCL2）出现异常的细胞自主产生，这会导致具有显著促肿瘤活性的巨噬细胞募集增加。在Lkb1驱动的子宫内膜癌小鼠模型中使Ccl2失活可减缓肿瘤进展并延长生存期。在人类原发性子宫内膜癌中，LKB1蛋白缺失与肿瘤细胞CCL2表达增加以及肿瘤微环境中巨噬细胞密度增加密切相关。这些数据表明CCL2是子宫内膜癌中LKB1缺失的强效效应因子，为治疗机会创造了潜在途径。
