LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment
Christopher G. Peña, Yuji Nakada, Hatice D. Saatcioglu, Gina M. Aloisio, Ileana Cuevas, Song Zhang, David S. Miller, Jayanthi S. Lea, Kwok-Kin Wong, Ralph J. DeBerardinis, Antonio L. Amelio, Rolf A. Brekken, Diego H. Castrillon
Christopher G. Peña, Yuji Nakada, Hatice D. Saatcioglu, Gina M. Aloisio, Ileana Cuevas, Song Zhang, David S. Miller, Jayanthi S. Lea, Kwok-Kin Wong, Ralph J. DeBerardinis, Antonio L. Amelio, Rolf A. Brekken, Diego H. Castrillon
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Research Article Oncology

LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment

Abstract

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.

Authors

Christopher G. Peña, Yuji Nakada, Hatice D. Saatcioglu, Gina M. Aloisio, Ileana Cuevas, Song Zhang, David S. Miller, Jayanthi S. Lea, Kwok-Kin Wong, Ralph J. DeBerardinis, Antonio L. Amelio, Rolf A. Brekken, Diego H. Castrillon

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Figure 8

Low LKB1 protein levels in primary human endometrial cancers are strongly correlated with high CCL2 expression and increased macrophage density.

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Low LKB1 protein levels in primary human endometrial cancers are strongl...
A human endometrial cancer TMA was stained and scored for each marker per the schematic in Supplemental Figure 6. A total of 175 separate cases of primary endometrial cancer were scored. Pair-wise correlations were evaluated by Kendall’s τ coefficient, with P values determined by 2-tailed t tests. (A) Heat maps showing significant negative correlations among grade 1 and grade 1–3 endometrial adenocarcinomas. (B) Top panels: number of cases with specific staining scores (grades 0–3) among tumors of different clinical stages (FIGO 1A, 1B, 1C). Of cases with more than 50% myometrial invasion (defined as stage 1C), the percentage with low LKB1 expression or high CCL2/CD68 expression was significantly increased. Bottom panels: number of cases with specific staining scores (grades 0–3) among tumors of different histopathological grades (grades 1, 2, 3). There was a significantly greater percentage of cases expressing low levels of LKB1 protein among high-grade tumors (n = 113). Additionally, there was a significantly greater percentage of cases expressing high levels of CCL2 (n = 113) and CD68 (n = 113) among high-grade tumors. *P < 0.005; **P < 0.001, Fisher’s exact t test.