To date, no specific marker exists for the detection of circulating tumor cell from different types of sarcomas, though tools are available for detection of circulating tumor cell (CTC) in peripheral blood of cancer patients for epithelial cancers. Here we report cell-surface vimentin (CSV) as an exclusive marker on sarcoma CTC regardless of the tissue origin of the sarcoma as detected by a novel monoclonal antibody. Utilizing CSV as a probe we isolated and enumerated sarcoma CTC with high sensitivity and specificity from the blood of patients bearing different types of sarcoma, validating their phenotype by single cell genomic amplification, mutation detection and fluorescence in situ hybridization. Our results establish the first universal and specific CTC marker described for enumerating CTC from different types of sarcoma, thereby providing a key prognosis tool to monitor cancer metastasis and relapse.

FGL2 augments glioma immunosuppression by increasing the expression levels of PD-1 and CD39, expanding the frequency of tumor-supportive M2 macrophages via the FcγRIIB pathway, and enhancing the number of MDSCs and CD39(+) regulatory T cells. Collectively, these results show that FGL2 functions as a key immune-suppressive modulator and has potential as an immunotherapeutic target for treating GBM.

The liver is the major metabolic organ and is subjected to constant attacks from chronic viral infection, uptake of therapeutic drugs, life behavior (alcoholic), and environmental contaminants, all of which result in chronic inflammation, fibrosis, and ultimately, cancer. Therefore, there is an urgent need to discover effective therapeutic agents for the prevention and treatment of liver injury; the ideal drug being a naturally occurring biological inhibitor. Here, we establish the role of IL30 as a potent anti-inflammatory cytokine which can inhibit inflammation-induced liver injury. In contrast, IL27, which contains IL30 as a subunit, is not hepatoprotective. Interestingly, IL30 is induced by the pro-inflammatory signal such as IL12 through IFNγ/STAT1 signaling. In animal models, administration of IL30 via a gene therapy approach prevents and treats both IL12-, IFNγ-, and Concanavalin A -induced liver toxicity. Likewise, immunohistochemistry analysis of human tissue samples revealed that IL30 is highly expressed in hepatocytes yet barely expressed in inflammation-induced tissue such as fibrous/connective tissue. These novel observations reveal a novel role of IL30 as a therapeutic cytokine that suppresses pro-inflammatory cytokine-associated liver toxicity.

Like many effective therapeutics, interleukin-12 (IL-12) therapy often causes side effects. Tumor targeted delivery may improve the efficacy and decrease the toxicity of systemic IL-12 treatments. In this study, a novel targeting approach was investigated. A secreted alkaline phosphatase (SEAP) reporter gene-based screening process was used to identify a mini-peptide which can be produced in vivo to target gene products to tumors. The coding region for the best peptide was inserted into an IL-12 gene to determine the antitumor efficacy. Affinity chromatography, mass spectrometry analysis, and binding studies were used to identify a receptor for this peptide. We discovered that the linear peptide VNTANST increased the tumor accumulation of the reporter gene products in five independent tumor models including one human xenogeneic model. The product from VNTANST-IL-12 fusion gene therapy increased accumulation of IL-12 in the tumor environment, and in three tumor models, VNTANST-IL-12 gene therapy inhibited distal tumor growth. In a spontaneous lung metastasis model, inhibition of metastatic tumor growth was improved compared to wild-type IL-12 gene therapy, and in a squamous cell carcinoma model, toxic liver lesions were reduced. The receptor for VNTANST was identified as vimentin. These results show the promise of using VNTANST to improve IL-12 treatments.

It is well known that the interleukin (IL)-27 receptor WSX1 is expressed in immune cells and induces an IL-27-dependent immune response. Opposing this conventional dogma, this study reveals a much higher level of WSX1 expression in multiple types of epithelial tumor cells when compared with normal epithelial cells. Expression of exogenous WSX1 in epithelial tumor cells suppresses tumorigenicity in vitro and inhibits tumor growth in vivo. Different from the role of WSX1 in immune cells, the antitumor activity of WSX1 in epithelial tumor cells is independent of IL-27 signaling but is mainly dependent on natural killer (NK) cell surveillance. Deficiency of either the IL-27 subunit EBV-induced gene 3 or the IL-27 receptor WSX1 in the host animals had no effect on tumor growth inhibition induced by WSX1 expression in tumor cells. Expression of WSX1 in epithelial tumor cells enhances NK cell cytolytic activity against tumor cells, whereas the absence of functional NK cells impairs the WSX1-mediated inhibition of epithelial tumor growth. The underlying mechanism by which WSX1 expression in tumor cells enhances NK cytolytic activity is dependent on up-regulation of NKG2D ligand expression. Our results reveal an IL-27-independent function of WSX1: sensitizing NK cell-mediated antitumor surveillance via a NKG2D-dependent mechanism. [Cancer Res 2009;69(13):5505-13]

Interleukin 30 (IL30), the p28 subunit of IL27, interacts with Epstein-Barr virus induced gene 3 to form IL27, which modulates both pro- and anti-inflammatory responses during autoimmune or infectious disease. It also acts as a natural antagonist of glycoprotein 130 (gp130), thereby attenuating the signals of other gp130-associated cytokines. IL30 regulation via LPS has been reported by others, but the intercellular communication that induces IL30 expression is unknown. Here, we show that treatment with anti-CD3/CD28 antibodies plus CpG oligodeoxynucleotides induces robust expression of IL30, whereas either treatment alone induces only low expression of IL30. This observation in vitro mirrors murine model in which administration of CpG under inflammatory conditions in vivo induces IL30 expression. This robust induction of IL30 occurs through the coordination of helper CD4+ T cells and innate immune cells (such as macrophages) and, to a lesser degree, B cells via the CD40/CD154 signaling pathway. These findings reveal a previously unrecognized mechanism that integrates signaling pathways from T cells and macrophages at the cellular level to induce IL30 expression.

Background The cellular and molecular etiology of unresolved chronic liver inflammation remains obscure. While mutant p53 has gain-of-function properties in tumors, the role of this protein in liver inflammation is unknown. Main Herein, mutant p53R172H is mechanistically linked to spontaneous and sustained liver inflammation and steatosis when combined with the absence of IL27 signaling (IL27RA), resembling the phenotype seen in non-alcoholic fatty liver (NAFLD) and non-alcoholic steatohepatitis (NASH) patients. Indeed, these mice develop with age hepatocyte necrosis, immune cell infiltration, fibrosis, micro- and macro-steatosis; however, these phenotypes are absent in mutant p53R172H or IL27RA−/− mice. Mechanistically, ETAR-positive macrophages are highly accumulated in the inflamed liver, and chemical inhibition of ETAR signaling reverses the observed phenotype and negatively regulates mutant p53 levels in macrophages. Conclusion The combination of mutant p53 and IL27RA−/− causes spontaneous liver inflammation, steatosis, and fibrosis in vivo, while either gene alone in vivo has no effects on the liver.

Inflammation plays an integral part in tumor initiation. Specifically, patients with colitis, pancreatitis, or hepatitis have an increased susceptibility to cancer. The activation, mutation, and overexpression of oncogenes have been well documented in cell proliferation and transformation. Recently, oncogenes were found to also regulate the inflammatory milieu in tumors. Similarly, the inflammatory milieu can promote oncogene activation. In this review, we summarize advances of the symbiotic relationship oncogene activation and inflammation in gastrointestinal tumors such as colorectal, hepatic, and pancreatic tumors. NF-κB and STAT3 are the two most common pathways that are deregulated via these oncogenes. Understanding these interactions may yield effective therapeutic strategies for tumor prevention and treatment.