Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.

Reprogrammed energy metabolism has become an emerging hallmark of cancer in recent years. Transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), encoded by the SLC7A8 gene, is a Na+-independent neutral amino acid transporter and is responsible for transporting neutral amino acids, including glutamine, which can activate mTOR. Previous studies have shown that LAT2 was overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains uncertain and elusive. The effects of LAT2 on biological behaviors were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated. We demonstrated that LAT2 emerged as an oncogenic protein and could decrease the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. The results of a survival analysis indicated that high expression levels of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, we found that gemcitabine combined with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, we demonstrated that LAT2 could regulate two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) to promote glycolysis and decrease gemcitabine (GEM) sensitivity in pancreatic cancer. Taken together, our data reveal that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease GEM sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.

Background: Chemoresistance is one of the main causes of poor prognosis in pancreatic cancer patients. Understanding the mechanisms implicated in chemoresistance of pancreatic cancer is critical to improving patient outcomes. Recent evidences indicate that the long noncoding RNAs (lncRNAs) are involving in chemoresistance of pancreatic cancer. However, the mechanisms of lncRNAs contribute to resistance in pancreatic cancer and remain largely unknown. The objective of this study is to construct a chemoresistance-related lncRNA-associated competing endogenous RNA (ceRNA) network of pancreatic cancer and identify the key lncRNAs in regulating chemoresistance of the network. Methods: Firstly, lncRNA expression profiling of gemcitabine-resistant pancreatic cancer cells was performed to identify lncRNAs related to chemoresistance by microarray analysis. Secondly, with insights into the mechanism of ceRNA, we used a bioinformatics approach to construct a chemoresistance-related lncRNAs-associated ceRNA network. We then identified the topological key lncRNAs in the ceRNA network and demonstrated its function or mechanism in chemoresistance of pancreatic cancer using molecular biological methods. Further studies evaluated its expression to assess its potential association with survival in patients with pancreatic cancer. Results: Firstly, we demonstrated that lncRNAs were dysregulated in gemcitabine-resistant pancreatic cancer cells. We then constructed a chemoresistance-related lncRNA-associated ceRNA network and proposed that lncRNA Homo sapiens glutathione S-transferase mu 3, transcript variant 2 and noncoding RNA (GSTM3TV2; NCBI Reference Sequence: NR_024537.1) might act as a key ceRNA to enhance chemoresistance by upregulating L-type amino acid transporter 2 (LAT2) and oxidized low-density lipoprotein receptor 1(OLR1) in pancreatic cancer. Further studies demonstrated that GSTM3TV2, overexpressed in gemcitabine-resistant cells, enhanced the gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. Mechanistically, we identified that GSTM3TV2 upregulated LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance. In addition, we revealed that the expression levels of GSTM3TV2 were significantly increased in pancreatic cancer tissues and were associated with poor prognosis. Conclusion: Our results suggest that GSTM3TV2 is a crucial oncogenic regulator involved in chemoresistance and could be a new therapeutic target or prognostic marker in pancreatic cancer.

Pancreatic cancer is one of the most lethal malignancies. Recent studies indicated that development of pancreatic cancer may be intimately connected with the microbiome. In this review, we discuss the mechanisms through which microbiomes affect the development of pancreatic cancer, including inflammation and immunomodulation. Potential therapeutic and diagnostic applications of microbiomes are also discussed. For example, microbiomes may serve as diagnostic markers for pancreatic cancer, and may also play an important role in determining the efficacies of treatments such as chemo- and immunotherapies. Future studies will provide additional insights into the various roles of microbiomes in pancreatic cancer.