Targeting STAT3 to Relieve Immune Suppression
Kujawski M., Zhang C, Herrmann A, Reckamp K, Scuto A, Jensen M, et al. Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects. Cancer Res 2010;70:9599–610.
Adoptive immune therapy with T cells has been used as a strategy to treat cancer; however, the tumor microenvironment largely dictates activity of these cells through expression of immunosuppressive molecules. Kujawski and colleagues have shown that enhanced activity of adoptively transferred CD8+ T cells can be achieved by inhibiting Stat3, either experimentally through genetic deletion or pharmacologically in vivo through treatment with the targeted therapeutic sunitinib, which inhibits Stat3 in both T cells and dendritic cells. Moreover, sunitinib reduced conversion of T cells into FoxP3+ TReg cells. These results illustrate that efficacy of immune therapy can be enhanced by targeted inactivation of critical regulatory gene products to block immunosuppressive properties within the tumor microenvironment.
‘Migration Signature’ for Pancreatic Ductal Adenocarcinoma
Balasenthil S, Chen N, Lott ST, Chen J, Carter J, Grizzle WE, et al. A migration signature and plasma biomarker Panel for pancreatic adenocarcinoma. Cancer Prev Res; Published OnlineFirst November 11, 2010; doi:10.1158/1940-6207.CAPR-10-0025.
Pancreatic ductal adenocarcinoma is a significant health problem with poor prognosis and a survival rate of approximately 5%. Currently, no reliable markers exist for early diagnostics and monitoring, which could help in guiding early therapy for this invariably fatal cancer. In the present study, Balasenthil and colleagues, through a functional genomic approach, scrutinized the human chromosome 3p12 region, alterations of which have been implicated as early events in many epithelial tumors, including pancreatic cancers. They identified a seven-gene panel (TNC, TFPI, TGFBI, SEL-1L, L1CAM, WWTR1, and CDC42BPA) that was differentially expressed across three different expression platforms, including pancreatic tumor/normal samples. In addition, results drawn from Ingenuity Pathway Analysis and literature searches suggest that this seven-gene panel functions in one network associated with cellular movement/morphology/development, indicative of a “migration signature” of the 3p pathway. Two secreted proteins from this panel, Tenascin C (TNC) and Tissue Factor Pathway Inhibitor (TFPI), were evaluated as plasma biomarkers along with CA-19-9, a commonly elevated marker for pancreatic cancer. Plasma ELISA assays for TFPI/TNC resulted in a combined area under the curve (AUC) of 0.88 and, with addition of CA19-9, a combined AUC for the three-gene panel (TNC/TFPI/CA19-9) was 0.99 with 100% specificity at 90% sensitivity and 97.22% sensitivity at 90% specificity. Validation studies using TFPI only in a blinded sample set increased the performance of CA19-9 alone from an AUC of 0.84 to 0.94 with the two-gene panel. This is an interesting 3p pathway-associated migration signature identified in pancreatic cancer. The signature gene panel, including the validated plasma biomarker, could be useful for further evaluation in large study cohorts, monitoring disease status of patients, and guiding clinical therapeutic applications.
What You See Is What You Have: Novel Approach for Imaging Metastases
Cancer is a progressive multistep process that can culminate in development of metastatic lesions that are difficult, and in the majority of cases, currently impossible to treat successfully. In this context, the ability to monitor and treat metastatic cancers effectively would be significantly enhanced through development of noninvasive imaging approaches. Bhang and colleagues have now documented that tumor-specific imaging of metastases can be accomplished by using the promoter region of progression elevated gene-3 (PEG-3) linked to an appropriate imaging modality, using either luciferase or herpes simplex virus 1 thymidine kinase. The PEG-3 promoter, derived from a rodent gene mediating tumor progression, was successfully used to selectively drive imaging reporters to enable detection of micrometastatic disease in mouse models of human melanoma and breast cancer using bioluminescence and radionuclide-based molecular imaging approaches. When one considers the cancer-specific expression of the PEG-3 promoter in multiple human cancers and its capacity for clinical translation, this approach, which involves systemic delivery of the construct using a nonviral vector, may represent a practical, new system for facilitating cancer imaging and therapy. Further clinical studies to define the safety and efficacy of this novel method are clearly warranted, and if successful, offer significant potential for early detection and diagnosis of cancer, defining appropriate treatment options, and monitoring efficacy.
Blood Vessels from Brain Tumor Stem Cells
Glioblastoma multiforme is likely to arise from cancer stem cells, with evidence in mice indicating that some glioblastoma tumors may arise from transformation of normal neural stem cells as well. Glioblastoma stem cells are in close contact with blood vessels. Does the close proximity of cancer stem cells to endothelial cells reflect a necessary interaction or a lineage relationship? To address this question, two groups of researchers, Ricci-Vitiani and colleagues and Wang and colleagues, separately analyzed the relationship between endothelial cells and cancer stem cells in glioblastoma tumors. Both groups independently found that tumor and vascular cells shared common genomic abnormalities in tumors and in vascular cells and showed that xenografted human glioblastoma cancer stem cells gave rise to tumors with human endothelial cells. These data indicate that glioblastoma stem cells give rise to both tumor and endothelial cells in glioblastoma multiforme.
Not All Brain Tumors Come from Stem Cells
A large body of evidence indicates that many glioblastoma multiforme tumors arise from cancer stem cells. The cell of origin for a related brain tumor, oligodendroglioma, remains less certain. Although the natural history of both tumors is dismal, oligodendroglioma stands in contrast to glioblastoma due to its sensitivity to cytotoxic chemotherapy. To address these differences, Persson and colleagues analyzed early regions of proliferation in the brain affected by oligodendroglioma, demonstrating proliferation in brain regions corresponding to progenitor cells, rather than normal neural stem cells. By fractionating murine and human primary oligodendroglial or astrocytic tumors, they demonstrated that oligodendroglioma arises from a progenitor rather than from a stem cell. Interestingly, normal progenitors in the brain are similar to oligodendrogliomas in their sensitivity to alkylating chemotherapy, whereas normal neural stem cells are similar to glioblastoma multiforme tumors in being resistant. Thus, oligodendroglioma tumors likely arise from a progenitor cell, with a progenitor rather than a stem cell origin contributing to the improved prognosis in patients.
RAS Regulates Tumor Development via Multiple Mechanisms
RAS is among the most prominent oncogenes in cancer, contributing to lung and pancreatic cancer, among others. How does RAS affect malignant progression? To address this question, Juntilla and colleagues used a mouse model for KRAS-induced lung cancer and reactivated p53 in established tumors. The tumors did not regress; however, reactivation of p53 was associated with decreased tumor grade. Activation of p53 in murine lung tumors was associated with high-level but not low-level RAS signal, suggesting limitations to reactivation of p53 in RAS-driven tumors. Does RAS signaling influence tumor-stromal interactions? In a different system, Lee and Bar-Sagi analyzed the ways in which RAS contributes to malignant progression in pancreatic cancer. They demonstrated that infiltrating immune cells induce senescence in primary pancreatic ductal epithelial cells and that activated RAS (acting through Twist) abrogates induction of p16 (Ink4a), bypassing induction of senescence and contributing to transformation.