Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma

Abstract

Mesenchymal stem cells (MSCs) possess the ability to migrate toward tumor sites and are regarded as promising gene delivery vehicles for cancer therapeutics. However, the factors that mediate this tropism have yet to be completely elucidated. In this study, through cytokine array analysis, chemokine CCL15 was found to be the most abundant protein differentially expressed in hepatocellular carcinoma (HCC) cell lines compared with a normal liver cell line. Serum CCL15 levels in HCC patients determined by enzyme linked immunosorbent assay were shown to be profoundly elevated compared with healthy controls. Immunohistochemical analysis indicated that CCL15 expression was much stronger in HCC tumor tissues than in adjacent nontumor tissues. Transwell migration assay suggested that CCL15 may be involved in chemotaxis of human MSCs (hMSCs) toward HCC in vitro and that this chemotactic effect of CCL15 is mediated via CCR1 receptors on hMSCs. Orthotopic animal models of HCC were established to investigate the role of CCL15 in hMSCs migration toward HCC in vivo. Both histological and flow cytometric analysis showed that significantly fewer hMSCs localized within 97H-CCL15-shRNA xenografts compared with 97H-green fluorescent protein xenografts after intravenous delivery. Finally, the possible effects of hMSCs on HCC tumor growth were also evaluated. Coculture experiments showed that hMSCs had no apparent effect on the proliferation of HCC cells in vitro In addition, systemic administration of hMSCs did not affect HCC tumor progression in vivo. Our data in this study help to elucidate the mechanism underlying the homing capacity of hMSCs toward HCC. STEM CELLS 2016;34:1112-1122 SIGNIFICANCE STATEMENTMesenchymal stem cells (MSCs) possess the ability to migrate toward tumor sites and are regarded as promising gene delivery vehicles for cancer therapeutics. In this study, HCC-derived CCL15 was demonstrated to be a chemoattractant for MSCs both in vitro and in vivo, and that this tropism of hMSCs for HCC is mainly mediated through the CCL15/CCR1 axis. Our data in the present study help to elucidate the mechanism underlying the homing capacity of hMSCs toward HCC and may be exploited to improve the therapeutic efficacy of hMSCs in the treatment of HCC.

CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma

“…Several studies have indicated a crucial role of CCL15 in tumor progression, including HCC, lung cancer, and colorectal cancer . It was reported that mothers against decapentaplegic homolog 4, bound directly to CCL15 gene promoter region to negatively regulate its expression in colorectal cancer .…”

“…In colorectal cancer, CCL15 was reported to recruit CCR1 + myeloid–derived suppressor cells and CCR1 + neutrophils to promote metastasis . Meanwhile, CCL15 could also attract a small proportion of bone marrow–derived mesenchymal stem cells toward HCC . Therefore, it appeared that the types of CCR1 + cells were diverse in different tumor microenvironments.…”

“…Several studies have indicated a crucial role of CCL15 in tumor progression, including HCC, lung cancer, and colorectal cancer. (24)(25)(26)(27)(28) It was reported that mothers against decapentaplegic homolog 4, bound directly to CCL15 gene promoter region to negatively regulate its expression in colorectal cancer. (24)(25)(26) Our present study indicated that genetic, epigenetic, and microenvironmental factors collectively governed CCL15 expression in HCC cells.…”

Skin-derived mesenchymal stem cells as quantum dot vehicles to tumors

“…Several studies [44][45][46] demonstrate the tendency of MSCs to migrate to the sites of the tumor. Therefore, to investigate whether skin MSCs possess the same properties, we simulated the migration of MSCs toward cancer cells (MDA-MB-231) and noncancerous breast epithelial cells (MCF-10A) using Transwell migration assay.…”

“…Such complexes have been already designed and tested as effective tools for pancreatic cancer. 93 Although we chose breast cancer as a tumor model, recent studies show the applicability of MSC-based therapy for the treatment of tumors of various locations, for example, ovarian, 94 liver, 46 lung, 95 and so on. A considerable amount of research has been done on glioma models, as MSCs are able to cross the blood-brain barrier and localize in intracranial neoplasms.…”