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Simple Summary Pancreatic cancer has the lowest survival rate of all malignancies. Understanding the interplay between tumor and stroma could lead to the development of new therapies. The metabolic role of interleukin 17B/interleukin 17B receptor (IL-17B/RB) has not been adequately studied in pancreatic cancer and is poorly understood. Here, we investigate the IL-17B/RB-mediated interactions between the tumor and the stroma. We analyze murine as well as human stromal and tumor cells, animal experiments with immunocompromised mice, and human cell lines with overexpression and knockdown of IL-17RB. We report that aberrant expression of IL-17B/RB in stromal pancreatic stellate cells (PSCs) accelerates tumor cell growth. IL-17B/RB-signaling supplies energy by increased oxidative phosphorylation (OXPHOS). Blocking IL-17B/RB to inhibit the tumor to stroma crosstalk could be a potential targeted therapy for pancreatic cancer. Abstract In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) signaling. Tumor-derived IL-17B carrying extracellular vesicles (EVs) activated stromal PSCs and induced the expression of IL-17RB. PSCs increased oxidative phosphorylation while reducing mitochondrial turnover. PSCs activated tumor cells in a feedback loop. Tumor cells subsequently increased oxidative phosphorylation and decreased glycolysis partially via IL-6. In vivo, IL-17RB overexpression in PSCs accelerated tumor growth in a co-injection xenograft mouse model. Our results demonstrate a tumor-to-stroma feedback loop increasing tumor metabolism to accelerate tumor growth under optimal nutritional conditions.

Simple Summary Esophageal cancer is one of the top ten most deadly cancers. Even when diagnosed in a curable stage, patients prognosis poor. One of the parameters that is very relevant for long-term survival is response to radio(chemo)therapy prior surgery. Complete response rates are between 24 and 50 percent. This puts more than a half of every esophageal cancer patient that is diagnosed in a non-metastasized stage at high risk of recurrence. To improve response rates of treatment regimens prior curative surgery is, therefore, a major challenge in treating esophageal cancer. Not only the response of the cancer cell itself to cancer therapy is determining patients’ fate. Cells around the tumor cells called the tumor microenvironment that together with the cancer cell constitute a malignant tumor are also involved in tumor progression and therapy response. This review depicts the most important parts of the esophageal cancer microenvironment, evaluates chances and challenges of current already established therapeutic concepts that target this microenvironment. It furthermore elucidates specific pathways that are potential valuable targets in the future. Abstract Esophageal cancer is among the top ten most deadly cancers worldwide with adenocarcinomas of the esophagus showing increasing incidences over the last years. The prognosis is determined by tumor stage at diagnosis and in locally advanced stages by response to (radio-)chemotherapy followed by radical surgery. Less than a third of patients with esophageal adenocarcinomas completely respond to neoadjuvant therapies which urgently asks for further strategies to improve these rates. Aiming at the tumor microenvironment with novel targeted therapies can be one strategy to achieve this goal. This review connects experimental, translational, and clinical findings on each component of the esophageal cancer tumor microenvironment involving tumor angiogenesis, tumor-infiltrating immune cells, such as macrophages, T-cells, myeloid-derived suppressor cells, and cancer-associated fibroblasts. The review evaluates the current state of already approved concepts and depicts novel potentially targetable pathways related to esophageal cancer tumor microenvironment.

Dickkopf-2 (DKK2) has been described as Wnt/beta-catenin pathway antagonist and its expression is mediated by micro RNA-221 (miRNA-221). So far, there is only limited data characterizing the role of DKK2 expression in esophageal cancer. A tissue micro array of 192 patients with esophageal adenocarcinoma was analyzed immunohistochemically for DKK2, miRNA-221 expression by RNA scope, and GATA6 amplification by fluorescence in-situ hybridization. The data was correlated with clinical, pathological and molecular data (TP53, HER2, c-myc, GATA6, PIK3CA, and KRAS amplifications). DKK2 expression was detectable in 21.7% and miRNA-221 expression in 33.5% of the patients. We observed no correlation between DKK2 or miRNA-221 expression and clinico-pathological data DKK2 expression was correlated with TP53 mutations and amplification of GATA6. We did not detect a survival difference in dependence of DKK2 for the total cohort, however, in patients without neoadjuvant treatment DKK2 expression correlated with a prolonged survival (median overall-survival 202 vs. 55 months, p = 0.012) which turned opposite in patients that underwent neoadjuvant treatment. High amounts of miRNA-221 were in trend associated with a prolonged overall-survival (p = 0.070). DKK2 as a Wnt antagonist is associated with prolonged survival in patients without neoadjuvant treatment and changes its prognostic value to the contrary in patients after neoadjuvant therapy. The modulatory effects of neoadjuvant treatment in connection with DKK2 expression are not fully understood, but when considering DKK2 as a tumor marker, it is necessary to see it in the context of neoadjuvant therapy.