Introduction to the role of microRNAs in cancer diagnosis, prognosis, and treatment.

During the past 30 years, it has become clear that cancer is a genetic disease caused, for the most part, by somatic genetic changes that either activate oncogenes or cause loss of function of tumor suppressor genes. The dogma was that all genes involved in cancer pathogenesis and progression, oncogenes and tumor suppressor genes, are encoding protein products. This view of cancer was shattered in 2002 when Calin et al showed that the major genetic alteration in chronic lymphocytic leukemia, a common hematologic malignancy affecting individuals older than 60 years, but not uncommon in individuals older than 40 years, consists in the loss of 2 microRNAs, miR-15a and miR-16-1, that reside in the same polycistronic RNA precursor encoded by a locus at 13q14, a chromosomal region often deleted in chronic lymphocytic leukemia. These findings suggested that genetic alterations in noncoding genes may also be responsible for cancer development and progression. After these seminal findings, Calin et al also showed that microRNA genes map precisely to chromosomal regions often involved in specific and recurrent chromosome alterations, such as deletions or gene amplifications, in a variety of human cancers. Since then, work in many different laboratories has shown specific dysregulation of microRNAs in many different tumors, and today, it is pretty clear that dysregulation of specific microRNAs occurs in all human malignancies. It has also become clear that, in most cases, such dysregulation is caused by the dysregulation of pathways and their related transcription factors that are involved in cancer pathogenesis. Thus, most of the microRNAs involved in cancer causation and progression have to be seen as downstream targets of pathways involved in cancer pathogenesis. Because of the tissue and cell type specificity of microRNA expression and because of the specific microRNA dysregulation in cancer, microRNAs can be exploited as powerful biomarkers for the diagnosis and prognosis of cancer and the monitoring of the success of therapy. MicroRNA dysregulation, however, can be detected not only in cancer tissue but also in blood (plasma and serum) of cancer patients, providing great opportunities for the development of noninvasive biomarkers for the diagnosis, prognosis, and monitoring of the progression and regression of tumors. Because microRNAs are always targetableVif they are lost, they can be replaced, and if they are overexpressed, they can be targeted for degradation by using antimicroRNAsVit is becoming clear that microRNA dysregulation can be targeted by microRNAs and antimicroRNAs as drugs. Finally, it has been shown, at first by Costinean et al, that dysregulation of microRNAs in mouse models can be exploited for the validation of the microRNA role in cancer pathogenesis. Such models can then be exploited for the development of microRNA/antimicroRNAYbased therapies of cancer or for the testing of anticancer drugs. Recently, it has also been shown that resistance to specific anticancer therapies is caused by the dysregulation of specific microRNAs and that such resistance can be overcome using microRNAs/ antimicroRNAs. Thus, the last few years have shown the existence of a new class of genes, noncoding, that are responsible, at least in part, for tumor development and progression and that their dysregulation can be used for the development of better diagnostic and prognostic tests. In addition, when the critical microRNAs involved in tumor development are identified, it should be possible to develop microRNAs/antimicroRNAs as drugs in cancer treatment. This volume consists of 9 articles providing compelling support for the role of microRNA dysregulation in cancer development and progression and for the use of microRNAs as biomarkers in cancer diagnosis and prognosis.