Esophageal Cancer Secretes BMP7 To Regulate Tumor Microenvironment Through The Promotion Of Fibroblasts Activation

Background:Esophageal cancer is one of the most common cancers all over the world,which is the sixth leading cause of cancer-related mortality.There are two main subtypes of esophageal cancer: esophageal adenocarcinoma(EAC)and esophageal squamous cell carcinoma(ESCC).Currently,the prognosis for esophageal cancer remains poor though the improvements in diagnostics and therapeutics.According to the reports,the five-year overall survival rate is only 15 to 25 percent,which is mainly attributable to late diagnosis and tendency for metastasis.With typical treatment still limited to surgical or endoscopic resection and chemoradiation,it is necessary to better understand the molecular pathogenesis of esophageal cancer for discovering new biomarkers and therapeutic targets.The advance of cancer is no longer being considered as an isolated incident which merely involves in the genetic mutation and irrepressible growth of cancer cells.Varied types of cytokines and growth factors secreted by the surrounding stromal cells and signal pathways induced by cell-cell interactions are considered to play critical roles in the tumorigenesis and metastasis.On one hand,a subpopulation of fibroblasts,which is called cancer-associated fibroblasts(CAF),is thought to actively contribute to the growth and invasion of the tumor cells by providing an irreplaceable tumor microenvironment(TME).On the other hand,Tumor cells can also secrete different molecules that act on the surrounding or distant fibroblasts,and then promote them to be CAF.It is becoming clearness that the cross-talk between the CAFs and the cancer cells has a critical role in the cancer progression,and catching on this mutual association may finally allow us to treat cancer patients by targeting CAF.Currently,there is increasing evidence that the cross-talk between CAF and tumor cells plays an important role in the progression of tumor.Hence,to explore the CAFs' function on esophageal premalignant condition,cancer origination,progression,metastasis and prognosis prediction could further provide certain understandings into its clinical application.Objective:Evaluating the roles of BMP7 on the functional regulation of fibroblast and investigating the cross-talk between the esophageal cancer cells and the CAF.Methods:1.The expression of BMP7 in esophageal carcinoma tissue was detected by immunohistochemical staining.The expression of BMP7 in esophageal cancer cell lines was detected by Western Blot.2.Immunofluorescence staining of esophageal carcinoma tissue was used to detect the presence of CAF in esophageal carcinoma.The expression of ?-SMA in esophageal carcinoma tissues from 160 patients was determined by immunohistochemistry staining.Combined with clinicopathological data,investigating the relationship between the expression of ?-SMA and the prognosis of esophageal cancer patients.3.Isolation and culture of stromal fibroblasts,in vitro cell culture experiments were conducted to study the effect of esophageal cancer cell lines on fibroblast activation.In vivo,the effect of esophageal cancer cells on the activation of fibroblasts was investigated by hypodermic tumor model of nude mice.4.MTT assay detect the role of CAF in promoting the proliferation of esophageal carcinoma cell lines.Results:1.BMP7 expression in esophageal carcinoma tissue and esophageal cancer cell lines,and the epression levels of BMP7 are different in different esophageal cancer tissues and esophageal cancer cell lines.2.As the most widely used marker of CAF,?-SMA expression was associated with poorer outcomes in patients with ESCC.Furthermore,clinicopathologically,tumor size,tumor depth and perineural invasion were signifcantly related to ?-SMA expression levels.3.The esophageal cancer cell lines with high expression levels of BMP7 could promote the activation of NF in vivo and in vitro,while the esophageal cancer cell lines with low expression levels could not.4.The proliferation of esophageal cancer cell lines(KYSE-150 and EC109)can be promoted by supernatant fluid of CAF.Conclusion:The cross-talk between the CAFs and the cancer cells has a critical role in the progression of esophageal cancer.The esophageal cancer with high expression levels of BMP7 could promote the activation of CAF,which could further promote the growth of esophageal cancer.