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Tumor metastasis comprises a series of coordinated events that culminate in dissemination of cancer cells to distant sites within the body representing the greatest challenge impeding effective therapy of cancer and the leading cause of cancer-associated morbidity. Cancer cells exploit multiple genes and pathways to colonize to distant organs. These pathways are integrated and regulated at different levels by cellular- and extracellular-associated factors. Defining the genes and pathways that govern metastasis can provide new targets for therapeutic intervention. Melanoma differentiation associated gene-9 (mda-9) (also known as Syntenin-1 and SDCBP (Syndecan binding protein)) was identified by subtraction hybridization as a novel gene displaying differential temporal expression during differentiation of melanoma. MDA-9/Syntenin is an established Syndecan binding protein that functions as an adaptor protein. Expression of MDA-9/Syntenin is elevated at an RNA and protein level in a wide-range of cancers including melanoma, glioblastoma, neuroblastoma, and prostate, breast and liver cancer. Expression is increased significantly in metastatic cancer cells as compared with non-metastatic cancer cells or normal cells, which make it an attractive target in treating cancer metastasis. In this review, we focus on the role and regulation of mda-9 in cancer progression and metastasis. [ABSTRACT FROM AUTHOR]

In principle, viral gene therapy holds significant potential for the therapy of solid cancers. However, this promise has not been fully realized and systemic administration of viruses has not proven as successful as envisioned in the clinical arena. Our research is focused on developing the next generation of efficacious viruses to specifically treat both primary cancers and a major cause of cancer lethality, metastatic tumors (that have spread from a primary site of origin to other areas in the body and are responsible for an estimated 90% of cancer deaths). We have generated a chimeric tropism‐modified type 5 and 3 adenovirus that selectively replicates in cancer cells and simultaneously produces a secreted anti‐cancer toxic cytokine, melanoma differentiation associated gene‐7/Interleukin‐24 (mda‐7/IL‐24), referred to as a Cancer Terminator Virus (CTV) (Ad.5/3‐CTV). In preclinical animal models, injection into a primary tumor causes selective cell death and therapeutic activity is also observed in non‐injected distant tumors, that is, “bystander anti‐tumor activity.” To enhance the impact and therapeutic utility of the CTV, we have pioneered an elegant approach in which viruses are encapsulated in microbubbles allowing “stealth delivery” to tumor cells that when treated with focused ultrasound causes viral release killing tumor cells through viral replication, and producing and secreting MDA‐7/IL‐24, which stimulates the immune system to attack distant cancers, inhibits tumor angiogenesis and directly promotes apoptosis in distant cancer cells. This strategy is called UTMD (ultrasound‐targeted microbubble‐destruction). This novel CTV and UTMD approach hold significant promise for the effective therapy of primary and disseminated tumors. [ABSTRACT FROM AUTHOR]

Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a cytokine belonging to the IL-10 family, displays cancer-specific apoptosis-inducing properties when delivered by a replication-incompetent adenovirus (Ad.mda-7) or as a GST-tagged recombinant protein (GST-MDA-7). Previous studies demonstrated that an adenovirus expressing M4, a truncated version of MDA-7/IL-24 containing amino acid residues 104–206, also induced similar cancer-specific apoptosis. We generated recombinant GST-M4 proteins and examined the potency of GST-MDA-7 and GST-M4 on a panel of epidermal growth factor receptor (EGFR) wild type and mutant non-small cell lung carcinoma (NSCLC) cells either as a single agent or in combination with a reversible EGFR inhibitor, Tarceva. The combination of either GST-MDA-7 or GST-M4 (∼0.1 µM) and Tarceva (10 µM), at sub-optimal apoptosis-inducing concentrations synergistically enhanced growth inhibition and apoptosis induction over that observed with either agent alone. The combination treatment also augmented inhibition of EGFR signaling, analyzed by phosphorylation of EGFR and its downstream effectors AKT and ERK1/2, over that with single-agent therapy. Tarceva enhanced GST-MDA-7 and GST-M4 toxicity in cells expressing mutated EGFR proteins that are resistant to the inhibitory effects of Tarceva. In total, these data suggest that combined treatment of NSCLC cells with an EGFR inhibitor can augment the efficacy of GST-MDA-7 and GST-M4 and that the EGFR inhibitor Tarceva may mediate this combinatorial effect by inhibiting multiple tyrosine kinases in addition to the EGFR. This approach highlights a potential new combinatorial strategy, which may prove beneficial for NSCLC patients with acquired resistance to EGFR inhibitors. J. Cell. Physiol. 215: 827–836, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]