Photodynamic therapy augments oxaliplatin-induced immunogenic cell death in colorectal cancer.

Colorectal cancer is one of the most frequently diagnosed cancers. Immunotherapy has been proven to be a potential treatment option for colorectal cancer. Colorectal cancer maintains immune escape by expressing low immunogenicity and following the tolerogenic cell death pathway. There is also emerging evidence that oxaliplatin and photodynamic therapy (PDT) can promote anti-tumor immunity. However, the effect of PDT combined with oxaliplatin on colorectal cancer remains elusive. Here, we analyzed the viability of HCT116 and DLD-1 cell lines after treatment with the combination of PDT and oxaliplatin. We found that the viability decreased significantly after the combination treatment. Meanwhile, we also detected that sinoporphyrin sodium (DVDMS)-derived PDT could amplify oxaliplatin-induced immunogenic cell death (ICD) in different colorectal cancer cell lines. More importantly, the combination of DVDMS-derived PDT and oxaliplatin presented strong immunogenic potential in immunocompetent BALB/c mice in the vaccination assay. Taken together, our data demonstrated that the combination of DVDMS-derived PDT and oxaliplatin is a potential novel therapy for colorectal cancer.

Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion.

Solid cancers like pancreatic ductal adenocarcinoma (PDAC), a type of pancreatic cancer, frequently exploit nerves for rapid dissemination. This neural invasion (NI) is an independent prognostic factor in PDAC, but insufficiently modeled in genetically engineered mouse models (GEMM) of PDAC. Here, we systematically screened for human-like NI in Europe's largest repository of GEMM of PDAC, comprising 295 different genotypes. This phenotype screen uncovered 2 GEMMs of PDAC with human-like NI, which are both characterized by pancreas-specific overexpression of transforming growth factor α (TGF-α) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGF-α upregulated CCL2 secretion from sensory neurons, which induced hyperphosphorylation of the cytoskeletal protein paxillin via CCR4 on cancer cells. This activated the cancer migration machinery and filopodia formation toward neurons. Disrupting CCR4 or paxillin activity limited NI and dampened tumor size and tumor innervation. In human PDAC, phospho-paxillin and TGF-α-expression constituted strong prognostic factors. Therefore, we believe that the TGF-α-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC.

Schwann cell-derived exosomes: Janus-faced mediators of regeneration and disease.

The phenotypic plasticity of Schwann cells (SCs) has contributed to the regenerative potential of the peripheral nervous system (PNS), but also pathological processes. This double-sided effect has led to an increasing attention to the role of extracellular vesicles (EVs) or exosomes in SCs to examine the intercellular communication between SCs and their surroundings. Here, we first describe the current knowledge of SC and EV biology, which forms the basis for the updates on advances in SC-derived exosomes research. We seek to explore in-depth the exosome-mediated molecular mechanisms involved in the regulation of SCs and their microenvironment. This review concludes with potential applications of SC-derived exosomes as delivery vehicles for therapeutics and biomarkers. The goal of this review is to emphasize the crucial role of SC-derived exosomes in the functional integration of the PNS, highlighting an emerging area in which there is much to explore and re-explore.

The Effect of Celiac Neurolysis and Splanchnicectomy on Survival in Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Intractable pancreatic pain is one of the most common symptoms of patients with pancreatic ductal adenocarcinoma (PDAC). Celiac neurolysis (CN) and splanchnicectomy were already described as effective methods to manage abdominal pain in unresectable PDAC, but their impact on overall survival (OS) has not yet been established. OBJECTIVE: We aimed to investigate the impact of CN and splanchnicectomy on the survival of patients with unresectable pancreatic cancer. METHODS: A systematic review of PubMed and Cochrane Library according to predefined searching terms was conducted in March 2020. Hazard ratios (HR) of OS data were calculated using the Mantel-Haenszel model for random effects or fixed effects. RESULT: Four randomized-controlled trials (RCTs) and 2 non-RCTs with a total of 2,507 patients were identified. The overall pooled HR did not reveal any relevant effect of CN and splanchnicectomy on OS (HR: 1.03; 95% CI: 0.81-1.32), which was also underlined by the sensitivity analysis of RCTs (HR: 1.0; 95% CI: 0.72-1.39) and non-RCTs (HR: 1.07; 95% CI: 0.71-1.63). However, subgroup analyses depending on tumor stage revealed that CN or splanchnicectomy was associated with a worsened OS in AJCC (American Joint Committee on Cancer) stage III patients with unresectable PDAC (HR: 1.22; 95% CI: 1.03-1.45), but nor for AJCC stage IV patients (HR: 1.27; 95% CI: 0.9-1.80). CONCLUSION: Although only few data are currently available, this systematic review with meta-analysis showed that in unresectable PDAC, CN or splanchnicectomy is associated with a worsened survival in stage III PDAC patients, with no effect on stage IV PDAC patients. These data call for caution in the usage of CN or splanchnicectomy in stage III PDAC and for further studies addressing this observation.

Innervated mouse pancreas organoids as an ex vivo model to study pancreatic neuropathy in pancreatic cancer.

Pancreatic cancer is characterized by bi-directional interactions between pancreatic cancer cells and stromal cells including neural cells. The absence of neural cells in pancreatic organoids limits the investigation of cell- cell interaction and tumor innervation. This protocol describes how to generate innervated wild type (WT) and Kras+/LSLG12D Trp53fl/f lp48+/Cre (KPC) murine pancreatic organoids. To specifically investigate neurogenesis, organoids are co-cultured with iPSCs-derived neural crest cells, while co-culture with dorsal root ganglia explants is used for comparing organoids with mature neurons. For complete details on the use and execution of this protocol, please refer to Huch et al. (2013), Boj et al. (2015), and Demir et al. (2014).

Clinicopathological Characteristics and Prognoses of Elderly Gastric Cancer Patients after R0 Resection: A Multicenter Study in China.

The number of elderly gastric cancer (GC) patients has been rapidly increasing worldwide, but inadequate understanding regarding elderly GC patients has led to the paucity of appropriate treatment decisions. Our study evaluates clinicopathological characteristics and prognoses of elderly GC patients after R0 resection. Overall, 1877 consecutive GC patients who underwent R0 gastrectomy at four centers were enrolled. We divided patients into three groups according to age: young, middle, and elderly. We then analyzed clinicopathological characteristics and prognoses. Compared to the middle-aged group, the elderly group had a higher male-to-female ratio and number of patients with cardiac GC, trend of more advanced pathological stage, lower ratio of poor to moderate tumor grade, and fewer patients who received adjuvant chemotherapy or chemoradiotherapy. Moreover, 5 yr disease-free survival and overall survival rates of elderly patients were significantly less than those of middle-aged patients. A Cox analysis of middle-aged and elderly patients revealed that age and adjuvant chemotherapy were independent prognostic factors. Adjuvant chemotherapy improved long-term survival of elderly patients with stage III cancer. Elderly GC patients who underwent R0 resection had unique characteristics and poor long-term survival. We found that subjects should be stratified into the three aforementioned age groups when analyzing survival rates of GC patients. In addition, reasonable adjuvant treatment is recommended for elderly patients.