Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches

Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient. The factors involved in chemoresistance include the development of a desmoplastic stroma which reprograms cellular metabolism, and both contribute to an impaired response to therapy. PDAC stroma is composed of immune cells, endothelial cells, and cancer-associated fibroblasts embedded in a prominent, dense extracellular matrix associated with areas of hypoxia and acidic extracellular pH. While multiple gene mutations are involved in PDAC initiation, this desmoplastic stroma plays an important role in driving progression, metastasis, and chemoresistance. Elucidating the mechanisms underlying PDAC resistance are a prerequisite for designing novel approaches to increase patient survival. In this review, we provide an overview of the stromal features and how they contribute to the chemoresistance in PDAC treatment. By highlighting new paradigms in the role of the stromal compartment in PDAC therapy, we hope to stimulate new concepts aimed at improving patient outcomes.

Activable Multi-Modal Nanoprobes for Imaging Diagnosis and Therapy of Tumors

Malignant tumors have become one of the major causes of human death, but there remains a lack of effective methods for tiny tumor diagnosis, metastasis warning, clinical efficacy prediction, and effective treatment. In this context, localizing tiny tumors via imaging and non-invasively extracting molecular information related to tumor proliferation, invasion, metastasis, and drug resistance from the tumor microenvironment have become the most fundamental tasks faced by cancer researchers. Tumor-associated microenvironmental physiological parameters, such as hypoxia, acidic extracellular pH, protease, reducing conditions, and so forth, have much to do with prognostic indicators for cancer progression, and impact therapeutic administrations. By combining with various novel nanoparticle-based activatable probes, molecular imaging technologies can provide a feasible approach to visualize tumor-associated microenvironment parameters noninvasively and realize accurate treatment of tumors. This review focuses on the recent achievements in the design of “smart” nanomedicine responding to the tumor microenvironment-related features and highlights state-of- the-art technology in tumor imaging diagnosis and therapy.

The death-inducing activity of RIPK1 is regulated by the pH environment

Receptor-interacting protein kinase 1 (RIPK1) is a serine/threonine kinase that dictates whether cells survive or die in response to the cytokine tumor necrosis factor (TNF) and other inflammatory stimuli. The activity of RIPK1 is tightly controlled by multiple posttranslational modification mechanisms, including ubiquitination and phosphorylation. Here, we report that sensitivity to TNF-induced, RIPK1-dependent cell death was tunable by the pH environment. We found that an acidic extracellular pH, which led to a concomitant decrease in intracellular pH, impaired the kinase activation of RIPK1 and autophosphorylation at Ser166. Consequently, formation of the cytosolic death-inducing complex II and subsequent RIPK1-dependent necroptosis and apoptosis were inhibited. By contrast, low pH did not affect the formation of membrane-anchored TNFR1-containing signaling complex (complex I), RIPK1 ubiquitination, and NF-κB activation. TNF-induced cell death in Ripk1−/− cells was not sensitive to pH changes. Furthermore, mutation of the conserved His151 abolished the pH dependence of RIPK1 activation, suggesting that this histidine residue functions as a proton acceptor to modulate RIPK1 activity in response to pH changes. These results revealed an unexpected environmental factor that controls the death-inducing activity of RIPK1.

ZnO Quantum Dots Modified by pH-Activated Charge-Reversal Polymer for Tumor Targeted Drug Delivery

In this paper, we reported a pH responsive nano drug delivery system (NDDS) based on ZnO quantum dots (QDs) for controlled release of drugs. Zwitterionic poly(carboxybetaine methacrylate) (PCBMA) and poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) were introduced to modify ZnO QDs, which can help enhance water stability, increase blood circulation time, and promote endocytosis. After tuning of PCBMA/PDMAEMA ratios, the ZnO@P(CBMA-co-DMAEMA) nanoplatform shows a sensitive switch from strong protein adsorption resistance (with negatively charged surface) at physiological pH to strong adhesion to tumor cell membranes (with positively charged surface) at the slightly acidic extracellular pH of tumors. Anti-cancer drug, Doxorubicin (DOX), molecules were demonstrated to be successfully loaded to ZnO@P(CBMA-co-DMAEMA) with a relatively large drug loading content (24.6%). In addition, ZnO@P(CBMA-co-DMAEMA) loaded with DOX can achieve lysosomal acid degradation and release of DOX after endocytosis by tumor cells, resulting in synergistic treatment of cancer, which is attributed to a combination of the anticancer effect of Zn2+ and DOX.