Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.

BackgroundLaparoscopic total gastrectomy (LTG) with Roux-en-Y (RY) is often accompanied by a series of complications. Uncut RY (URY) can effectively reduce Roux stasis syndrome (RSS) in laparoscopic distal gastrectomy. To determine whether totally LTG (TLTG) with URY for gastric cancer (GC) can replace RY in short-term and long-term prognosis.MethodsThis comparative retrospective study selected GC patients from 2016 to 2022. The patients were divided into URY group and RY group. Cox multivariate proportional hazard regression analysis was used to explore the independent prognostic factors. Propensity score matching (PSM) was used to reduce bias.ResultsA total of 100 GC patients met the inclusion criteria. Compared to RY group, URY group showed significant advantages in operation time and length of hospital stay. In addition, URY group can significantly reduce short-term and long-term complications, especially RSS. The 1-, 3- and 5-year progression free survival (PFS) of URY group and RY group were 90.4% vs. 67.8% (P=0.005), 76.6% vs. 52.6% (P=0.009) and 76.6% vs. 32.8% (P<0.001), respectively. After PSM, the advantage of URY in PFS was verified again, while there was no significant difference in overall survival (OS) between the two groups. Cox multivariate analysis suggested that lower RSS was associated with better PFS.ConclusionsTLTG with URY for GC helps control disease progression, speed up recovery and reduce short and long-term complications, especially RSS.

Tumor heterogeneity is an important feature of malignant tumors, and cell subpopulations may positively interact to facilitate tumor progression. Studies have shown that hypoxic cancer cells possess enhanced metastatic capacity. However, it is still unclear whether hypoxic cancer cells may promote the metastasis of normoxic cells, which have greater access to the blood circulation. When cocultured with hypoxic CRC cells or treated with hypoxic CRC cell-derived CM, normoxic CRC cells possessed increased metastatic capacity. Furthermore, hypoxic CRC cell-derived CM was enriched in interleukin 8. Hypoxic CRC cell-derived CM and recombinant human IL-8 both enhanced the metastatic capacity of normoxic cells by increasing the phosphorylation of p65 and then by inducing epithelial-mesenchymal transition. Knockdown of IL-8 in hypoxic CRC cells or the use of an anti-IL-8 antibody attenuated the CM- or rhIL-8-induced prometastatic capacity of normoxic CRC cells. Inhibition or knockdown of p65 abrogated IL-8-induced prometastatic effects. Most importantly, hypoxia-treated xenograft tumors enhanced the metastasis of normoxic CRC cells. Hypoxic CRC cell-derived IL-8 promotes the metastatic capacity of normoxic cells, and novel therapies targeting the positive interactions between hypoxic and normoxic cells should be developed.