The mda-7/IL-24 cDNA was isolated almost a decade ago in a screen for genes differentially upregulated following growth arrest and terminal differentiation of a human melanoma cell line employed as an in vitro cell differentiation model. The underlying rationale for the screen was that oncogenesis arises from a cellular dedifferentiation process culminating in uncontrolled proliferation and acquisition of invasive and metastatic potential. Identification of genes upregulated during the process of reactivation of faulty or inoperational differentiation maintenance programs was postulated to have cancer gene therapeutic potential. In this context, it is heartening to note that mda-7/IL-24 has made a methodical and progressive journey, from an unidentified novel sequence with little homology to known genes at its time of isolation to currently having the status of a molecule belonging to the IL-10-related family of cytokines, with considerable cancer gene therapeutic potential. Extensive in vitro and in vivo human tumor xenograft studies have established its transformed cell apoptosis-inducing capacity in various model systems. It has recently taken an important step for a candidate cancer gene therapeutic molecule, in the ultimate goal of benchtop to clinic, by being currently utilized in human Phase I/II clinical trials. This review provides a current perspective of our understanding of mda-7/IL-24, including established and more recent information about the molecular properties, specificity of anti-tumor-cell apoptosis-inducing activity, and underlying mechanisms of this action relative to its cancer gene therapeutic potential.
Bibliographical noteFunding Information:
The present studies were supported in part by National Institutes of Health Grants CA35675, CA88906, CA97318, CA98172, NS31492, and DK52825; DOD Breast Cancer Grant DAMD17-03-1-0290; the Lustgarten Foundation for Pancreatic Cancer Research; the Samuel Waxman Cancer Research Foundation; and the Chernow Endowment. P.B.F. is the Michael and Stella Chernow Urological Cancer Research Scientist in the Departments of Pathology, Urology, and Neurosurgery, Columbia University Medical Center, College of Physicians and Surgeons, and a SWCRF Investigator. P.D. is the Universal, Inc., Professor in Signal Transduction Research at Virginia Commonwealth University. We are indebted to the numerous contributions of our colleagues who have contributed to our current understanding of the anti-tumor properties and mechanism of action of mda-7/IL-24.