Mesenchymal stem cells enhance growth and metastasis of colon cancer

Abstract

Recently, mesenchymal stem cells (MSCs) were reported to migrate to tumor stroma as well as injured tissue. We examined the role of human MSCs in tumor stroma using an orthotopic nude mice model of KM12SM colon cancer. In in vivo experiments, systemically injected MSCs migrated to the stroma of orthotopic colon tumors and metastatic liver tumors. Orthotopic transplantation of KM12SM cells mixed with MSCs resulted in greater tumor weight than did transplantation of KM12SM cells alone. The survival rate was significantly lower in the mixed-cell group, and liver metastasis was seen only in this group. Moreover, tumors resulting from transplantation of mixed cells had a significantly higher proliferating cell nuclear antigen labeling index, significantly greater microvessel area and significantly lower apoptotic index. Splenic injection of KM12SM cells mixed with MSCs, in comparison to splenic injection of KM12SM cells alone, resulted in a significantly greater number of liver metastases. MSCs incorporated into the stroma of primary and metastatic tumors expressed a-smooth muscle actin and platelet-derived growth factor receptor-b as carcinoma-associated fibroblast (CAF) markers. In in vitro experiments, KM12SM cells recruited MSCs, and MSCs stimulated migration and invasion of tumor cells through the release of soluble factors. Collectively, MSCs migrate and differentiate into CAFs in tumor stroma, and they promote growth and metastasis of colon cancer by enhancing angiogenesis, migration and invasion and by inhibiting apoptosis of tumor cells.Mesenchymal stem cells (MSCs) are characterized by their ability to self-renew and differentiate into tissues of mesodermal origin, including bone, cartilage and adipose and connective tissues. Thus, they contribute to tissue regeneration.

Impact of Mesenchymal Stem Cell secreted PAI-1 on colon cancer cell migration and proliferation

“…It is now well established that MSCs migrate to and engraft at the site of many tumour types, including colorectal tumours [6], with conflicting reports on a pro-or anti-tumorigenic role [22]. Due to the remarkable tumour-specific homing capacity of MSCs, they may play a role as tumour targeted delivery agents [22].…”

“…However, the majority of studies employed an excess of MSCs to CCCs and are therefore an uncertain reflection of the physiological environment [9]. Shinagawa et al [6] observed that, following systemic injection via the tail vein, MSCs were functionally incorporated into the colorectal cancer tumour stroma where they displayed morphology and distribution similar to those of carcinoma-associated fibroblasts indicating a potential role in promoting tumorigenesis.…”

“…MSCs are nonhematopoietic, multipotent cells which are known to be actively recruited to the site of tumours, including colorectal tumours and their metastases [5,6,7]. Despite this, our knowledge of colon cancer cell-MSC interactions remains limited, and the role of MSCs within colon tumours has yet to be elucidated.…”

Mesenchymal Stem/Stromal Cells Exert Trophic Effect on Colorectal Cancer Metastasis to the Liver

“…Extensive studies have demonstrated that MSCs can migrate to the tumor site and incorporate into its microenvironment [23,24]. It has also been reported that MSCs migrate to colorectal tumors [25,26]. The common approach to study the homing of MSCs into tumor is transplanting culture expanded MSCs into animal models bearing tumor [24].…”

Human Mesenchymal Stem Cells Migrate toward Colon Cancer Partially Regulated by HMGB1

“…However, Karnoub et al suggested that MSCs have a supportive effect on tumor progression showing that co-injection of MSCs with breast cancer cell-line led to a higher degree of metastasis, but this effect was not significant in local tumor growth [20]. Also, the supportive effect on tumor growth by MSCs has been reported in different cancers such as colon cancer, lymphoma, and melanomas [47][48][49]. In contrast, several reports showed that MSCs may have a suppressive role in tumor development via p38 mitogen-activated protein kinases (MAPK) or by cell fusion [50,51].…”