Role of the Microenvironment in Gastrointestinal Tumors

Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China Fujian Key Laboratory of Integrative Medicine in Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, China Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China Department of Oncology, Ludwig Maximillian University of Munich, Munich, Germany Department of Oncology, Mayo Clinic, Minneapolis, MN, USA Department of Gastroenterology, Augusta University, Augusta, GA, USA

e gastrointestinal (GI) tract maintains a complex environment with diverse epithelial and nonepithelial cell types that regulate discrete and distant processes. Pathogens such as H. pylori and inflammatory conditions such as colitis, Barrett's esophagus, and pancreatitis are linked to GI cancers, and recent studies have shown that a targeted mutation in a specific cell type with or without inflammation can be sufficient to initiate cancer. Recent studies using nextgeneration sequencing to determine molecular subtypes have expanded our understanding of GI cancers, and efforts to go beyond basic pathological assessment including multigene biomarkers, machine learning algorithms, and organoid drug screens are underway with promising results. For therapy, nucleoside analogs, targeted inhibitors, and monoclonal antibodies have demonstrated positive but often limited results in the clinic. New therapies such as anti-PD1 immunotherapy have thus far shown benefit in subsets of patients such as those with microsatellite instability-high tumors, but have not yet delivered the transformational results seen in other cancers. In order to develop effective new therapies for GI cancers and accurately classify patient risk, an improved knowledge of molecular signaling and cell-cell interactions within the tumor microenvironment (TME) is needed. Importantly, in the current clinical context, a more complete understanding of how TME components modulate resistance to therapy and antitumor immunity will be fundamental to improving patient treatment options and outcomes. is special issue seeks to improve understanding of the molecular, cellular, and pathological characteristics of the TME in GI cancers.
In the paper by D. Qu et al., differential activities of cancer stem cell marker doublecortin-like kinase 1's isoforms in pancreatic cancer are described. Importantly, they confirm previous findings that DCLK1 can be coimmunoprecipitated with KRAS and demonstrate that DCLK1 is capable of activating RAS. ey support these findings with molecular, bioinformatic, and functional analyses of downstream pathways PI3K/AKT/MTOR and demonstrate the therapeutic use of DCLK1 monoclonal antibody using in vivo mouse models.
ese results further elucidate the functional mechanisms of an important GI CSC marker. C. He et al. also focused on pancreatic cancer and evaluated the effect of irreversible electroporation on immunologic characteristics in patients with locally advanced disease.
eir clinical findings demonstrate a prognostic value for CD8+ T cells in this context. ey conclude that this may have value as a prognostic tool in pancreatic cancer. investigated the prognostic potential for GLIS2 in gastric cancer. In the context of radiotherapy, low expression of GLIS2 predicted notable radiosensitivity, which might find use in improving the precision of gastric cancer radiotherapy. Whereas Md. N. Uddin et al. and H. Sun et al. utilized meta-analysis and mRNA expression to derive their respective signatures, and C. Just et al. opted to focus on small noncoding miRNAs. ey performed a retrospective study of 33 patients receiving neoadjuvant chemotherapy for esophagogastric junction adenocarcinoma using a 96-well array of miRNAs with known malignant roles. ey found differential expressions of   ese include cytokine and chemokine signaling, tumorstromal interactions, specific, mechanisms of metastasis, epigenetic influences, exosomal miRNAs, and immune checkpoint.

Conflicts of Interest
e editors declare they have no relevant conflicts of interest.