Bone marrow-derived mesenchymal stromal cells promote colorectal cancer cell death under low-dose irradiation.

BACKGROUND: Radiotherapy remains one of the cornerstones to improve the outcome of colorectal cancer (CRC) patients. Radiotherapy of the CRC not only help to destroy cancer cells but also remodel the tumour microenvironment by enhancing tumour-specific tropism of bone marrow-derived mesenchymal stromal cell (BM-MSC) from the peripheral circulation. However, the role of local MSCs and recruited BM-MSC under radiation were not well defined. Indeed, the functions of BM-MSC without irradiation intervention remained controversial in tumour progression: BM-MSC was previously shown to modulate the immune function of major immune cells, resulting in an impaired immunological sensitivity and to induce an increased risk of tumour recurrence. In contrast, it could also secrete various cytokines and possess anticancer effect. METHODS: Three co-cultivation modules, 3D culture modules, and cancer organoids were established. The induction of cytokines secretion in hBM-MSCs after irradiation was analysed by ELISA array and flow cytometry. AutoMac separator was used to separate hBM-MSC and CRC automatically. Cells from the co-cultured group and the control group were then irradiated by UV-C lamp and X-ray. Proliferation assay and viability assay were performed. RESULTS: In this study, we show that BM-MSCs can induce the EMT progression of CRC cells in vitro. When irradiated with low doses of ultraviolet radiation and X-rays, BM-MSCs show an anti-tumour effect by secreting certain cytokine (TNF-α, IFN-γ) that lead to the inhibition of proliferation and induction of apoptosis of CRC cells. This was further verified in a 3D culture model of a CRC cell in vitro. Furthermore, irradiation on the co-culture system induced the cleavage of caspase3, and attenuated the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase in cancer cells. The signal pathways above might contribute to the cancer cell death. CONCLUSIONS: Taken together, we show that BM-MSC can potentially promote the effect of radiotherapy in CRC.

Prognostic Value of Preoperative Serum Carcinoembryonic Antigen and Carbohydrate Antigen 19-9 After Resection of Ampullary Cancer.

BACKGROUND: The purpose of this study is to investigate the prognostic value of pre-resection serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 after resection of ampullary cancer (AC) in consideration of intestinal (IT) and pancreatobiliary (PT) subtypes. METHODS: Overall survival (OS) analysis of patients undergoing curative resection of ampullary cancer. RESULTS: Elevated preoperative CEA (P = 0.013) and CA 19-9 levels (P = 0.030) were significant prognostic factors. Subgroup analysis, however, showed both markers having prognostic value only for the IT subgroup. Pre-resection CEA within normal range identified a subgroup of IT patients with an excellent median survival of 145 months. Compared to other AC patients, this low-risk ITCEA- subpopulation was characterized by less frequent advanced pT stages (pT3/pT4, 41 vs. 62%; P = 0.047) and lymph node involvement (pN+, 30 vs. 65%; P = 0.001). OS of this subgroup was significantly better compared to other AC patients (145 vs. 25 months; HR = 3.8; P < 0.001). By multivariate survival analysis, the patient age, the PT subtype, and an elevated pre-resection serum CEA value were identified as independent prognostic variables. CONCLUSIONS: In AC, the histomorphologic subclassification is highly relevant regarding the prognostic value of preoperative serum CEA and CA 19-9. IT-patients with normal preoperative CEA represent a favorable subgroup with excellent long-term survival.