Jinghong Xu

γδT17 Cells Promote the Accumulation and Expansion of Myeloid-Derived Suppressor Cells in Human Colorectal Cancer

Development of cancer has been linked to chronic inflammation, particularly via interleukin-23 (IL-23) and IL-17 signaling pathways. However, the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer (CRC) remain poorly defined. Here, we demonstrate that innate γδT (γδT17) cells are the major cellular source of IL-17 in human CRC. Microbial products elicited by tumorous epithelial barrier disruption correlated with inflammatory dendritic cell (inf-DC) accumulation and γδT17 polarization in human tumors. Activated inf-DCs induced γδT17 cells to secrete IL-8, tumor necrosis factor alpha, and GM-CSF with a concomitant accumulation of immunosuppressive PMN-MDSCs in the tumor. Importantly, γδT17 cell infiltration positively correlated with tumor stages and other clinicopathological features. Our study uncovers an inf-DC-γδT17-PMN-MDSC regulatory axis in human CRC that correlates MDSC-meditated immunosuppression with tumor-elicited inflammation. These findings suggest that γδT17 cells might be key players in human CRC progression and have the potential for treatment or prognosis prediction.

miRNA-27b Targets Vascular Endothelial Growth Factor C to Inhibit Tumor Progression and Angiogenesis in Colorectal Cancer

Colorectal cancer (CRC) is one of the most prevalent cancers globally and is one of the leading causes of cancer-related deaths due to therapy resistance and metastasis. Understanding the mechanism underlying colorectal carcinogenesis is essential for the diagnosis and treatment of CRC. microRNAs (miRNAs) can act as either oncogenes or tumor suppressors in many cancers. A tumor suppressor role for miR-27b has recently been reported in neuroblastoma, while no information about miR-27b in CRC is available. In this study, we demonstrated that miR-27b expression is decreased in most CRC tissues and determined that overexpression of miR-27b represses CRC cell proliferation, colony formation and tumor growth in vitro and in vivo. We identified vascular endothelial growth factor C (VEGFC) as a novel target gene of miR-27b and determined that miR-27b functioned as an inhibitor of tumor progression and angiogenesis through targeting VEGFC in CRC. We further determined that DNA hypermethylation of miR-27b CpG islands decreases miR-27b expression. In summary, an anti-tumor role for miR-27b and its novel target VEGFC in vivo could lead to tumor necrosis and provide a rationale for developing miR-27b as a therapeutic agent.

Arginine Starvation Impairs Mitochondrial Respiratory Function in ASS1-Deficient Breast Cancer Cells

Tumors that cannot make arginine undergo mitochondrial dysfunction in the absence of extracellular arginine and die by autophagy. Starved to Death by Lack of Arginine Some breast tumors have low abundance of argininosuccinate synthetase 1 (ASS1), an enzyme involved in the synthesis of the amino acid arginine. Although ASS1 deficiency enhances the growth of these tumors, these cells are sensitive to depletion of external arginine. ADI-PEG20 (pegylated arginine deiminase), a modified form of a microbial enzyme, metabolizes arginine. Qiu et al. found that in various breast cancer cell lines that were deficient in ASS1, addition of ADI-PEG20 to the medium induced widespread mitochondrial dysfunction, which in turn triggered autophagy, an adaptive catabolic process that can lead to cell death if unchecked. In mice, ADI-PEG20 treatment slowed the growth of tumors formed from ASS1-deficient breast cancer cells only if these cells could undergo autophagy. Low ASS1 abundance in tumor samples from patients with breast cancer correlated with low survival rates, suggesting that treatments that induce arginine starvation may be beneficial in patients with ASS1-deficient breast cancers. Autophagy is the principal catabolic response to nutrient starvation and is necessary to clear dysfunctional or damaged organelles, but excessive autophagy can be cytotoxic or cytostatic and contributes to cell death. Depending on the abundance of enzymes involved in molecule biosynthesis, cells can be dependent on uptake of exogenous nutrients to provide these molecules. Argininosuccinate synthetase 1 (ASS1) is a key enzyme in arginine biosynthesis, and its abundance is reduced in many solid tumors, making them sensitive to external arginine depletion. We demonstrated that prolonged arginine starvation by exposure to ADI-PEG20 (pegylated arginine deiminase) induced autophagy-dependent death of ASS1-deficient breast cancer cells, because these cells are arginine auxotrophs (dependent on uptake of extracellular arginine). Indeed, these breast cancer cells died in culture when exposed to ADI-PEG20 or cultured in the absence of arginine. Arginine starvation induced mitochondrial oxidative stress, which impaired mitochondrial bioenergetics and integrity. Furthermore, arginine starvation killed breast cancer cells in vivo and in vitro only if they were autophagy-competent. Thus, a key mechanism underlying the lethality induced by prolonged arginine starvation was the cytotoxic autophagy that occurred in response to mitochondrial damage. Last, ASS1 was either low in abundance or absent in more than 60% of 149 random breast cancer biosamples, suggesting that patients with such tumors could be candidates for arginine starvation therapy.

β-catenin overexpression in the nucleus predicts progress disease and unfavourable survival in colorectal cancer: a meta-analysis.

Background β-catenin plays a key role in the progression of colorectal cancer (CRC). However, its prognostic significance for patients with CRC remains controversial. Methodology Identical search strategies were used to search relevant literatures in the PubMed, Embase and Web of Science databases. The correlation between β-catenin expression and clinicopathological features and prognosis was analyzed. Principal Findings A total of 18 studies met the inclusion criteria, which comprised 3665 cases. Meta-analysis suggested that β-catenin overexpression in the nucleus was significantly associated with disease free survival (DFS) (n = 541 in 3 studies; HR = 1.87, 95% CI: 1.28–2.71; Z = 3.26; P = 0.001) and overall survival (OS) for CRC patients (n = 2630 in 10 studies; HR = 1.55, 95% CI: 1.12–2.14; Z = 2.62; P = 0.009). However, there was no significant association between β-catenin expression in the cytoplasm and OS (n = 1327 in 3 studies; HR = 1.04, 95% CI: 0.88–1.24, Z = 0.46, P = 0.643). The combined odds ratio (OR) of β-catenin in the nucleus indicated that β-catenin overexpression was associated with advanced stage CRC (n = 950 in 7 studies; OR = 0.71, 95% CI: 0.53–0.94; Z = 2.35; P = 0.019) and metastasis of CRC (n = 628 in 5 studies; OR = 0.49, 95% CI: 0.25–0.96, Z = 2.06, P = 0.039). β-catenin overexpression in the nucleus had no correlation with the tumor site (colon or rectum), differentiation grade, lymph node status or depth of invasion. The pooled ORs were 1.09 (95% CI: 0.41–2.91, Z = 0.18, P = 0.856), 1.27(95% CI: 0.76–2.10, Z = 0.92, P = 0.357), 0.71(95% CI: 0.46–1.09, Z = 1.58, P = 0.115) and 0.82(95% CI: 0.4–1.68, Z = 0.53, P = 0.594). Conclusions This study showed that β-catenin overexpression in the nucleus, rather than in the cytoplasm, appeared to be associated with progress disease and a worse prognosis for CRC patients.

Ex vivo expanded human circulating Vδ1 γδT cells exhibit favorable therapeutic potential for colon cancer

Gamma delta T (γδT) cells are innate-like lymphocytes with strong, MHC-unrestricted cytotoxicity against cancer cells and show a promising prospect in adoptive cellular immunotherapy for various malignancies. However, the clinical outcome of commonly used Vγ9Vδ2 γδT (Vδ2 T) cells in adoptive immunotherapy for most solid tumors is limited. Here, we demonstrate that freshly isolated Vδ1 γδT (Vδ1 T) cells from human peripheral blood (PB) exhibit more potent cytotoxicity against adherent and sphere-forming human colon cancer cells than Vδ2 T cells in vitro. We also develop an optimized protocol to preferentially expand Vδ1 T cells isolated from PB of both healthy donors and colon cancer patients by in vitro short-term culture with phytohemagglutinin (PHA) and interleukin-7 (IL-7). Expanded Vδ1 T cells highly expressed cytotoxicity-related molecules, chemokine receptors and cytokines with enhanced cytolytic effect against adherent and sphere-forming colon cancer cells in a cell-to-cell contact dependent manner. In addition, PHA and IL-7 expanded Vδ1 T cells showed proliferation and survival advantage partly through an IL-2 signaling pathway. Furthermore, ex vivo expanded Vδ1 T cells also restrained the tumor growth and prolonged the tumor-burdened survival of human colon carcinoma xenografted mice. Our findings suggest that human PB Vδ1 T cells expanded by PHA and IL-7 are a promising candidate for anticancer adoptive immunotherapy for human solid tumors such as colon cancer.

Exome Capture Sequencing of Adenoma Reveals Genetic Alterations in Multiple Cellular Pathways at the Early Stage of Colorectal Tumorigenesis

Most of colorectal adenocarcinomas are believed to arise from adenomas, which are premalignant lesions. Sequencing the whole exome of the adenoma will help identifying molecular biomarkers that can predict the occurrence of adenocarcinoma more precisely and help understanding the molecular pathways underlying the initial stage of colorectal tumorigenesis. We performed the exome capture sequencing of the normal mucosa, adenoma and adenocarcinoma tissues from the same patient and sequenced the identified mutations in additional 73 adenomas and 288 adenocarcinomas. Somatic single nucleotide variations (SNVs) were identified in both the adenoma and adenocarcinoma by comparing with the normal control from the same patient. We identified 12 nonsynonymous somatic SNVs in the adenoma and 42 nonsynonymous somatic SNVs in the adenocarcinoma. Most of these mutations including OR6X1, SLC15A3, KRTHB4, RBFOX1, LAMA3, CDH20, BIRC6, NMBR, GLCCI1, EFR3A, and FTHL17 were newly reported in colorectal adenomas. Functional annotation of these mutated genes showed that multiple cellular pathways including Wnt, cell adhesion and ubiquitin mediated proteolysis pathways were altered genetically in the adenoma and that the genetic alterations in the same pathways persist in the adenocarcinoma. CDH20 and LAMA3 were mutated in the adenoma while NRXN3 and COL4A6 were mutated in the adenocarcinoma from the same patient, suggesting for the first time that genetic alterations in the cell adhesion pathway occur as early as in the adenoma. Thus, the comparison of genomic mutations between adenoma and adenocarcinoma provides us a new insight into the molecular events governing the early step of colorectal tumorigenesis.

A Minor (<50%) Signet-Ring Cell Component Associated with Poor Prognosis in Colorectal Cancer Patients: A 26-Year Retrospective Study in China

Background We performed a retrospective study to determine the cancer-specific survival of colorectal cancer patients with a component of signet-ring cells or mucin comprising < 50% of the tumor mass. Methods A total of 2454 patients seen in our hospital from 1985 to 2011 were retrospectively studied. The patients were divided into five groups according to type of cancer: signet-ring cell carcinoma (with > 50% signet-ring cell, n = 36), partial signet-ring cell carcinoma (with < 50% signet-ring cell, n = 28), mucinous adenocarcinoma (with > 50% mucin lacking signet-ring cell, n = 267), partial mucinous adenocarcinoma (with < 50% mucin lacking signet-ring cell, n = 145), and classic adenocarcinoma (with absence of either mucin or signet-ring cell, n = 1978). Results Patients with > 50% or < 50% signet-ring cell had the lowest 5-year survival rates (35.5% and 29.7%, respectively), followed by patients with > 50% mucin (48.8%). Patients who had partial mucinous adenocarcinoma with < 50% mucin and classic adenocarcinoma patients had the highest 5-year survival rates (64.8% and 65.3%, respectively). Stratified and multivariate analysis showed that signet-ring cell carcinoma, partial signet-ring cell carcinoma and mucinous adenocarcinoma were independent predictors of decreased survival (hazard ratio 1.699, P = 0.016; hazard ratio 2.182, P = 0.005; hazard ratio 1.532, P < 0.001; respectively), and partial mucinous adenocarcinoma was not (hazard ratio 1.137, P = 0.431). Conclusions Patients with a component of signet-ring cells, regardless of the extent, had poor prognoses. Patients with mucinous adenocarcinoma containing >50% mucin had poor prognoses as well, whereas those with < 50% mucin had survival rates similar to those of classic adenocarcinoma patients. Therefore, in clinical practice, patients with a component of signet-ring cells, regardless of the extent, should be given significant clinical attention.

A Case Report of Gastrointestinal Hemorrhage and Perforation During Apatinib Treatment of Gastric Cancer.

AbstractApatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which shows good efficacy and safety in clinical trials for chemotherapy-refractory gastric cancer patients. Till now, there is no case report after apatinib came in the market.We presented a 55-year-old Chinese woman with advanced gastric cancer, who received apatinib after failure of second-line chemotherapy. On the 19th day of apatinib administration, she suffered from gastrointestinal hemorrhage. Then, her condition rapidly deteriorated to gastrointestinal perforation. Although the patient received timely medical and surgical treatment, she finally died of septic shock.Although apatinib shows exciting efficacy and good tolerance in phase II and III clinical trials, this novel targeted drug should be prescribed carefully and close clinical monitoring is needed when using it.

Clinicopathologic distribution of KRAS and BRAF mutations in a Chinese population with colorectal cancer precursor lesions

Investigating the clinical features and corresponding histomorphologic and molecular profiles of precursor lesions of colorectal cancer in a natural population provides new insights into the nature of colorectal cancer, uncovers new screening markers and establishes new prevention strategies for colorectal cancer. In this study, 4302 patients with at least one colorectal polyp from a large colorectal cancer screening program were evaluated and genetic mutations in either KRAS or BRAF were detected in 495 patients. The population-based mutation rates of KRAS and BRAF genes in colorectal polyps within this Chinese patient population were 21.8% and 12.1% respectively. Interestingly, considerable variability in the KRAS and BRAF mutations rates were found among different types of polyps. In a multivariate analysis, presence of villous histology and high-grade dysplasia was associated with KRAS mutations (OR, 3.0; 95% CI, 1.7-5.4 and OR, 3.5; 95% CI 1.9-6.5, respectively), while serrated adenomas and hyperplastic polyps were associated with BRAF V600E mutations (OR, 20.6; 95% CI, 8.2–51.8 and OR, 11.9; 95% CI 4.9–29.0, respectively). KRAS mutations may, in part, drive the histologic progression of adenomas toward a villous histology and higher grades of dysplasia. Mutant BRAF may, in part, drive the histologic progression of adenomas toward serrated histology. Dysplasia may arise from hyperplastic polyps, resulting in the formation of serrated adenomas and potentially the development of colorectal carcinoma.

Metachronous Primary Adenocarcinoma of Lung During Adjuvant Imatinib Mesylate Therapy for Gastrointestinal Stromal Tumor of Stomach: A Case Report.

AbstractGastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in gastrointestinal tracts; however, the synchronous or metachronous coexistence of GIST with additional primary malignancy is not common.Here, we present an unusual case of gastric GIST with metachronous primary lung adenocarcinoma diagnosed during his adjuvant treatment with oral receptor tyrosine kinase inhibitor imatinib mesylate (400 mg daily). After 6-month use of imatinib, the patient suffered from dry cough and dyspnea. Subsequent lung biopsy demonstrated adenocarcinoma with diffuse interstitial changes.Our research emphasizes the possibility of an additional primary tumor with GIST, and reminds the clinicians to strengthen the surveillance of the additional cancer during the follow-up of GIST patients.