LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment
Christopher G. Peña, … , Rolf A. Brekken, Diego H. Castrillon
Christopher G. Peña, … , Rolf A. Brekken, Diego H. Castrillon
Published September 28, 2015
Citation Information: J Clin Invest. 2015;125(11):4063-4076. https://doi.org/10.1172/JCI82152.
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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 5

TAMs in Lkb1-driven endometrial cancers promote invasion and accelerate tumor progression.

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TAMs in Lkb1-driven endometrial cancers promote invasion and accelerate ...
Tumor-bearing Lkb1–/– animals were treated with liposomal PBS (n = 4) or liposomal clodronate (n = 4) for 9 weeks. (A) Confirmation of systemic macrophage depletion. Among diverse organs, only spleen showed decrease in mass following the clodronate regimen, as expected (macrophages make up a significant percentage of cells in the spleen). (B) F4/80 immunohistochemistry of uterine tissue section confirming macrophage depletion following treatment with clodronate. (C) H&E staining showing greatly decreased myometrial invasion in clodronate-treated Lkb1–/– mice. e, endometrium; m, myometrium; dashed lines, endometrial/myometrial interface; asterisks, invasive tumor glands. Note that endometrial glands are normally present only in the endometrium; hence, the greatly decreased myometrial involvement following clodronate is consistent with slowed tumor progression. (D) Tumor burden, as determined by uterine weight at conclusion of treatment. There was a significant reduction in tumor mass in clodronate-treated animals. *P < 0.01, Student’s t test. (E) Gross photographs of uteri at conclusion of treatment. Weights for uteri in grams shown in lower left-hand corner. Scale bars: 50 μm (B and C). Error bars = SEM.