The objective of this project is to develop an in vitro biomimetic human esophageal tumor tissue model for preclinical research on esophageal cancer. Esophageal cancer, a deadly cancer with no effective treatments, is the sixth leading cause of cancer-related deaths worldwide. Despite many years of research to improve the treatment outcomes of patients with esophageal cancer, the overall five-year survival rate of esophageal cancer patients remained only 18.8% in 2017. The limited progress in treating esophagus cancer patients is related to the limitations of current in vitro and in vivo esophageal cancer study models to some degrees, as those in vitro 2D cancer cell culture models or in vivo xenograft animal models differ greatly from the human esophageal cancer microenvironment. There is no suitable in vitro human esophageal cancer model available to study new strategies of drug screening, the function of a drug-eluting stent, and molecular mechanism of cancer cell lymph metastasis. The severe lack of in vitro human esophageal cancer models has impeded the breakthrough development of new therapeutic strategies for the deadly disease. To change the situation, we propose to develop an esophageal tumor tissue engineering model using a decellularized pig esophagus in a three-dimensional (3D) culture system. This 3D rotatory wall vessel bioreactor (RVWB) can support tumor cell growth and form a mimicking tumor tissue. We hypothesize that a 3D mimicking human esophageal tumor tissue model can be formed in the RVWB tissue culture system for esophageal cancer studies. To test this hypothesis, we propose the following specific aims: First, we will characterize the human esophageal cancer cells mono-cultured in the 3D tissue culture system (Aim 1). We will then co-culture esophageal cancer cells and stromal cell fibroblast, and then validate the 3D esophageal tumor tissue model (Aim 2). If successful, the study will enable us to establish an in vitro biomimetic human esophageal cancer model, which will bring about great promise to basic and applied esophageal cancer research, and promote the development of new targeting therapeutic strategies. This project will be a stepping-stone for our long-term goal to establish a clinically-relevant esophageal tumor model for drug screening, cancer stent, and metastasis molecular mechanism studies.
The lack of in vitro human esophageal cancer models has severely hindered the progress and development of new esophageal cancer therapeutic approaches. In this study we will develop a new in vitro human esophageal cancer tissue model, which will have not only the capability of recapitulating the in vivo human esophageal cancer microenvironment but also the ability to provide a three-dimensional structure for: (1) testing of the anti-tumor function of a new drug-eluting stent; (2) drug screening; and (3) analysis of molecular mechanisms of esophageal cancer cell metastasis.
