Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.

Metabolism rewiring is an important hallmark of cancers. Being one of the most abundant free amino acids in the human blood, glutamine supports bioenergetics and biosynthesis, tumor growth, and the production of antioxidants through glutaminolysis in cancers. In glutamine dependent cancer cells, more than half of the tricarboxylic/critic acid (TCA) metabolites are derived from glutamine. Glutaminolysis controls the process of converting glutamine into TCA cycle metabolites through the regulation of multiple enzymes, among which the glutaminase shows the importance as the very first step in this process. Targeting glutaminolysis via glutaminase inhibition emerges as a promising strategy to disrupt cancer metabolism and tumor progression. Here, we review the regulation of glutaminase and the role of glutaminase in cancer metabolism and metastasis. Furthermore, we highlight the glutaminase inhibitor based metabolic therapy strategy and their potential applications in clinical scenarios.

Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer.

Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy.

Background: Colon cancer is largely implicated in elderly patients (age ≥ 60 years). The prognosis of patients diagnosed with the M1b stage is vastly poor. Marital and insurance status has been considered important prognostic factors in various cancer types. However, how these factors influence elderly patients with stage M1b colon cancer remains to be explored. This study aims to uncover the role of marital and insurance status in the survival of elderly patients with stage M1b colon cancer. Methods: We retrieved data for patients diagnosed with stage M1b colon cancer between 2010 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database. Our analysis of the clinicopathological features, overall survival (OS), and cancer-specific survival (CSS) was based on the marital and insurance status, respectively. Results: In sum, 5709 stage M1b colon cancer patients with complete information from SEER were enrolled for analysis. The OS and CSS of the Non-married group were poorer compared to that of the Married group. The OS and CSS of the Uninsured group were poorer than both of the Insured group and Medicaid group. However, OS was comparable between Uninsured group and Medicaid groups. The findings allude that marital and insurance status potentially impact the long-term survival of elderly patients with M1b colon cancer. The subgroup survival analyses revealed the lowest risk for death among the Insured Married group based on the comparison of the OS and CSS across all other groups. Moreover, Univariate and multivariate analyses revealed race, marital status, surgery, and chemotherapy as independent predictors for OS, whereas insurance status, surgery,and chemotherapy were independent predictors for CSS in elderly patients with M1b colon cancer. Conclusion: The marital and insurance status greatly impact the survival of elderly patients with M1b colon cancer. Therefore, it is imperative to provide more support to this vulnerable patient group who are lonely and uninsured, particularly in the psychological and health insurance aspect.

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.