Sherven Sharma

PGE2-Driven Expression of c-Myc and OncomiR-17-92 Contributes to Apoptosis Resistance in NSCLC

Aberrant expression of microRNAs (miRNA) with oncogenic capacities (oncomiRs) has been described for several different malignancies. The first identified oncomiR, miR-17-92, is frequently overexpressed in a variety of cancers and its targets include the tumor suppressor PTEN. The transcription factor c-Myc (MYC) plays a central role in proliferative control and is rapidly upregulated upon mitogenic stimulation. Expression of c-Myc is frequently deregulated in tumors, facilitating proliferation and inhibiting terminal differentiation. The c-Myc–regulated network comprises a large number of transcripts, including those encoding miRNAs. Here, prostaglandin E2 (PGE2) exposure rapidly upregulates the expression of the MYC gene followed by the elevation of miR-17-92 levels, which in turn suppresses PTEN expression, thus enhancing apoptosis resistance in non–small cell lung cancer (NSCLC) cells. Knockdown of MYC expression or the miR-17-92 cluster effectively reverses this outcome. Similarly, miR-17-92 levels are significantly elevated in NSCLC cells ectopically expressing COX-2. Importantly, circulating miR-17-92 was elevated in the blood of patients with lung cancer as compared with subjects at risk for developing lung cancer. Furthermore, in patients treated with celecoxib, miR-17-92 levels were significantly reduced. These data demonstrate that PGE2, abundantly produced by NSCLC and inflammatory cells in the tumor microenvironment, is able to stimulate cell proliferation and promote resistance to pharmacologically induced apoptosis in a c-Myc and miR-17-92–dependent manner. Implications: This study describes a novel mechanism, involving c-Myc and miR-17-92, which integrates cell proliferation and apoptosis resistance. Mol Cancer Res; 12(5); 765–74. ©2014 AACR.

Lung Cancer and Immune Dysfunction

Lung cancer accounts for more than 28% of all cancer deaths each year, and is the leading cause of cancer-related mortality in the United States (1). Despite focused research in conventional therapies, the 5-year survival rate remains at 14%, and has improved only minimally in the past 25 years. Newly discovered molecular mechanisms in the pathogenesis of lung cancer provide novel opportunities for targeted therapies of non-small-cell lung cancer (NSCLC) (2,3). Immune-based targeted therapies have focused on the elicitation of specific tumor antigen-directed responses. Although various methods of immune stimulation have been attempted for the treatment of lung cancer, none have proven to be reliably effective (4). In contrast, immune-based therapies have proven more successful in melanoma and renal cell carcinoma (RCC) (5,6),leading to the misconception that thoracic malignancies are nonimmunogenic and are not amenable to immunologic interventions. However, protective immunity is now known to be generated against non-immunogenic murine tumors (7,8). These studies suggest that a tumor’s apparent lack of immunogenicity indicates a failure to elicit an effective host response rather than a lack of tumor antigen (TA) expression (9,10). Accordingly, a new paradigm has emerged that focuses on generating antitumor responses by therapeutic vaccination (11,12). In this setting, vaccination refers to an intervention that unmasks TAs, leading to generation of specific host-immune responses against the tumor.

Lung Tumor Microenvironment and Myelomonocytic Cells

The lung tumor microenvironment consists of tumor cells, stroma, blood vessels, immune infiltrates and the extracellular matrix. Genetic alterations in oncogenes and tumor suppressor genes or epigenetic changes in the tumor that modulate tumor growth and invasion into the surrounding tissue orchestrate the persistence of inflammatory infiltrates. These cellular infiltrates modulate tumor development and progression. The infiltrates vary by size and composition in diverse tumor types and at different stages of tumor development. The lung tumor programs the cellular infiltrates and dysregulates inflammation to sustain tumor growth, progression and hypo responsiveness of the tumor. Characterization of the complex interactions among the infiltrates and lung cancer will aid in defining their role in tumor progression. This understanding will be important for the development of novel anticancer therapies. Although this is not a trivial undertaking, the information garnered will take us a step closer to personalized medicine. If we know an individual’s lung tumor inflammatory infiltrates, we will be able to predict the risk of tumor progression and then give specific treatment to reprogram the tumor microenvironment to control the disease.