Cancer as a tissue: The significance of cancer-stromal interactions in the development, morphogenesis and progression of human upper digestive tract cancer.

We review the significance of cancer-stromal interactions (CSIs) in the development, morphogenesis and progression of human gastric and esophageal cancer based on the data obtained from co-culture experiments. Orthotopic fibroblasts in the gastric cancer stroma not only promoted their growth by cancer cells but were also responsible for the mobility, morphogenesis and epithelial-to-mesenchymal transition (EMT) of the cancer cells through CSI. Bone marrow-derived mesenchymal stem cells could be part of the origin of cancer-associated fibroblasts (CAFs) of the gastric cancer providing an advantageous microenvironment for the restoration of cancer stem cells with the induction of the EMT. Tumor-associated macrophages (TAMs) may differentiate from bone marrow-derived monocytes/macrophages within the tumor microenvironment of esophageal cancer and participate in the growth and the progression of esophageal squamous cell carcinomas (ESCCs). Macrophages infiltrated into the intraepithelial neoplastic lesions of the esophagus may function as a biological promoter by promoting the growth and motility of squamous epithelia. Tumor cells build up "cancer as a tissue" by taking advantage of the existing network of growth factors, cytokines and chemokines through the interactions of TAMs, CAFs and cancer cells themselves.