Zhi Qiang Wu

Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy.

BACKGROUND Stereotactic body radiation therapy (SBRT) is postulated to enhance the recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment, which promote tumor recurrence. The aim of this study is to determine the molecular mechanisms behind SBRT stimulating MSC migration and differentiation. METHODS In vitro, mediated factors and migrated MSCs (post-SBRT) were generated. In vivo, bone-marrow derived MSCs were identified and harvested from green fluorescent protein (GFP)-expressing transgenic male mice and transplanted into sub-lethally irradiated recipient female mice to establish a model of bone marrow transplantation. Lewis lung carcinoma and malignant melanoma-bearing recipient mice were treated with SBRT, 14 Gy/1 fraction. The migration and differentiation potential of MSCs were characterized. RESULTS SBRT increased the release of stromal cell derived factor-1α (SDF-1α) and platelet-derived growth factor-B (PDGF-B) by tumor cells; these ligands bound to chemokine (C-X-C motif) receptor 4 (CXCR4) and platelet-derived growth factor receptor-β (PDGFR-β), respectively, on circulating bone marrow-derived MSCs, resulting in engraftment of the MSCs into the tumor parenchyma. The newly-homed MSCs differentiated into pericytes, which induced the tumor vasculogenesis, and promoted tumor regrowth. Targeted therapies, AMD3100 and imatinib abrogated MSC homing, vasculogenesis, and tumor regrowth. CONCLUSION Bone-marrow derived MSCs migrate to the tumor parenchyma and differentiate into pericytes, inducing tumor vasculogenesis after SBRT, and promoting tumor recurrence. MSC migration and maturation may be abrogated with AMD3100 and imatinib. This novel treatment strategy warrants clinical investigation.

Targeting pyruvate kinase M2 contributes to radiosensitivity of non-small cell lung cancer cells in vitro and in vivo

Aerobic glycolysis, a metabolic hallmark of cancer, is associated with radioresistance in non-small cell lung cancer (NSCLC). Pyruvate kinase M2 isoform (PKM2), a key regulator of glycolysis, is expressed exclusively in cancers. However, the impact of PKM2 silencing on the radiosensitivity of NSCLC has not been explored. Here, we show a plasmid of shRNA-PKM2 for expressing a short hairpin RNA targeting PKM2 (pshRNA-PKM2) and demonstrate that treatment with pshRNA-PKM2 effectively inhibits PKM2 expression in NSCLC cell lines and xenografts. Silencing of PKM2 expression enhanced ionizing radiation (IR)-induced apoptosis and autophagy in vitro and in vivo, accompanied by inhibiting AKT and PDK1 phosphorylation, but enhanced ERK and GSK3β phosphorylation. These results demonstrated that knockdown of PKM2 expression enhances the radiosensitivity of NSCLC cell lines and xenografts as well as may aid in the design of new therapies for the treatment of NSCLC.

Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy.

While the mechanisms underlying apoptosis and autophagy have been well characterized over recent decades, another regulated cell death event, necroptosis, remains poorly understood. Elucidating the signaling networks involved in the regulation of necroptosis may allow this form of regulated cell death to be exploited for diagnosis and treatment of cancer, and will contribute to the understanding of the complex tumor microenvironment. In this review, we have summarized the mechanisms and regulation of necroptosis, the converging and diverging features of necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy, as well as attempts to exploit this newly gained knowledge to provide therapeutics for cancer.

Stereotactic body radiation therapy for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph nodes or postoperative stump including pancreatic stump and other stump

Background and aim The aim of this study is to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) using CyberKnife in the treatment of patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Patients and methods Between October 1, 2006 and May 1, 2015, patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery were enrolled and treated with SBRT at our hospital. The primary end point was local control rate after SBRT. Secondary end points were overall survival, time to symptom alleviation, and toxicity, assessed using the Common Terminology Criteria for Adverse Events version 4.0. Results Twenty-four patients with 24 lesions (17 abdominal lymph nodes and seven stumps) were treated with SBRT, of which five patients presented with abdominal lymph nodes and synchronous metastases in the liver and lung. The 6-, 12-, and 24-month actuarial local control rates were 95.2%, 83.8%, and 62.1%, respectively. For the entire cohort, the median overall survival from diagnosis and SBRT was 28.9 and 12.2 months, respectively. Symptom alleviation was observed in eleven of 14 patients (78.6%) within a median of 8 days (range, 1–14 days) after SBRT. Nine patients (37.5%) experienced Common Terminology Criteria for Adverse Events version 4.0 grade 1–2 acute toxicities; one patient experienced grade 3 acute toxicity due to thrombocytopenia. Conclusion SBRT is a safe and effective treatment for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Further studies are needed before SBRT can be recommended routinely.

Multimodality therapy is recommended for limited-stage combined small cell esophageal carcinoma

Background and aim Limited-stage combined small cell esophageal carcinoma (LS-C-SCEC) is a rare, poorly understood, underdiagnosed disease, with components of both small cell esophageal cancer and non–small cell esophageal cancer. We investigated the optimal treatment strategy and prognostic factors in patients with LS-C-SCEC. Patients and methods LS-C-SCEC patients included in the analysis (from our hospital and the literature) were treated between January 1966 and December 2013. Patient treatment strategies included surgery (S), chemotherapy (CT), and radiation therapy (RT). The primary end point was overall survival (OS); the secondary end points included tumor complete response rates, patterns of failure, and toxicity. Kaplan–Meier curves were compared with the log-rank test. Univariate and multivariate analyses were used to determine prognosticators for OS. Results A total of 72 patients were included in the analysis: 24 (33%) from our hospital and 48 (67%) from the literature. The median OS of all patients was 15.0 months. Patients who received CT had a significantly longer median OS than did those who did not (OS 22.8 months vs 10.0 months) (P=0.03). Patients treated with multimodality therapy (including RT+CT [18%], S+CT [40%], or S+RT+CT [17%]) vs monotherapy (typically, S [18%]) had significantly improved OS (15.5 months vs 9.3 months) (P=0.02) and complete response rates. On multivariate analysis, tumor location (upper third of the esophagus) and type of treatment (monotherapy) were the only factors predictive of poor OS. Conclusion Multimodality therapy (including RT+CT, S+CT, or S+RT+CT) improves OS for patients with LS-C-SCEC compared with monotherapy (typically, S). Additional studies are necessary to personalize multimodal treatment approaches to individual patients.