New approaches for modelling cancer mechanisms in the mouse

Abstract

Mouse models of human cancer are vital to our understanding of the neoplastic process, and to advances in both basic and clinical research. Indeed, models of many of the major human tumours are now available and are subject to constant revision to more faithfully recapitulate human disease. Despite these advances, it is important to recognize that limitations do exist to the current range of models. The principal approach to modelling has relied upon the use of constitutive gene knockouts, which can often result in embryonic lethality, can potentially be affected by developmental compensation, and which do not mimic the sporadic development of a tumour expanding from a single cell in an otherwise normal environment. Furthermore, simple knockouts are usually designed to lead to loss of protein function, whereas a subset of cancer-causing mutations clearly results in gain of function. These drawbacks are well recognized and this review describes some of the approaches used to address these issues. Key amongst these is the development of conditional alleles that precisely mimic the mutations found in vivo, and which can be spatially and tissue-specifically controlled using 'smart' systems such as the tetracycline system and Cre-Lox technology. Examples of genes being manipulated in this way include Ki-Ras, Myc, and p53. These new developments in modelling mean that any mutant allele can potentially be turned on or off, or over-or under-expressed, in any tissue at any stage of the life-cycle of the mouse. This will no doubt lead to ever more accurate and powerful mouse models to dissect the genetic pathways that lead to cancer.

A non-canonical function of telomerase RNA in the regulation of developmental myelopoiesis in zebrafish

“…These results point to a non-canonical role of TR in myelopoiesis and suggest its probable involvement in the regulation of neutrophil function. This apparent discrepancy with TR-deficient mice, which do not show impaired myelopoiesis independently of telomere shortening, may be due to developmental and/or physiological compensations, which probably do not exist in humans [36][37][38] . TR-deficient neutrophils were recruited to wounds similarly to wild types.…”

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

“…In the case of more subtle molecular changes, however, we cannot completely exclude a potential contribution of MMTV-Cre on the expression of some genes. This is one of the many limitations of Cre-loxP technology (reviewed in Maddison and Clarke, 2005).…”

Raf kinases: Oncogenesis and drug discovery

“…Animal models of human cancer have contributed significant insights into the mechanisms of tumor formation and progression 64,65 and are indispensable tools for drug discovery. 66 During the early days of Raf kinase research, infection or transduction of newborn mice with retroviruses or retroviral vectors harbouring either wild-type or mutant Raf kinases were instrumental to prove their transforming potential.…”