Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis.

Metabolic reprogramming in cholangiocarcinoma

“…It has recently been demonstrated that tumour cells metabolically communicate with stromal cells predominantly in the primary tumour microenvironment. 71 Crosstalk between inflamed lymphatic endothelial cells (LECs) and CCA cells by the CXCL5-CXCR2 axis 72 induces alterations of mitochondrial respiration and glycolysis in tumour cells. Notably, CXCL5 directly induces lactate production, glucose uptake and generation of mitochondrial ROS in CCA cells but also increases metabolic gene expression in LECs.…”

“…Significant alterations in the cellular bioenergetics of LECs predispose patients to pro-lymphangiogenic signalling that promotes lymph node metastasis. 72 These lines of evidence paved the way for strategies to target metabolic communications for improved cancer treatments (Fig. 1).…”

CXCL5: A coachman to drive cancer progression

“…The progression of lung cancer is accelerated by the proliferation, movement, and diffusion of tumor cells. CXCL5 has also been reported to promote tumor progression in different tumors such as gastric cancer ( 60 ), liver cancer ( 62 ), bladder cancer ( 65 ), prostate cancer ( 68 ), nasopharyngeal carcinoma, intrahepatic cholangiocarcinoma ( 58 ), osteosarcoma ( 64 ), cholangiocarcinoma ( 59 ), papillary thyroid carcinoma ( 69 ), and renal cell carcinoma ( 71 ). Notably, CXCL5 also induces the development, metastasis, and drug resistance of bladder cancer.…”

Translational Value of Tumor-Associated Lymphangiogenesis in Cholangiocarcinoma

“…Upon CXCR2 stimulation, cancer cells show changes in mitochondrial respiration and in glycolysis, along with the induction of reactive oxygen species, and an increase in glucose uptake and lactate production. In addition, in response to LECs, CCA cells overexpress MMPs, particularly MMP1 and MMP21, resulting in matrix remodeling and further enhancing CCA cell migration and metastasis [ 71 ]. Likely, these molecular mechanisms may favor tumor cell invasion of the lymphatic vasculature and subsequent metastasis to regional lymph nodes.…”