Weaknesses and Pitfalls of Using Mice and Rats in Cancer Chemoprevention Studies

Abstract

Many studies, using different chemical agents, have shown excellent cancer prevention efficacy in mice and rats. However, equivalent tests of cancer prevention in humans require decades of intake of the agents while the rodents' short lifespans cannot give us information of the long-term safety. Therefore, animals with a much longer lifespan should be used to bridge the lifespan gap between the rodents and humans. There are many transgenic mouse models of carcinogenesis available, in which DNA promoters are used to activate transgenes. One promoter may activate the transgene in multiple cell types while different promoters are activated at different ages of the mice. These spatial and temporal aspects of transgenes are often neglected and may be pitfalls or weaknesses in chemoprevention studies. The variation in the copy number of the transgene may widen data variation and requires use of more animals. Models of chemically-induced carcinogenesis do not have these transgene-related defects, but chemical carcinogens usually damage metabolic organs or tissues, thus affecting the metabolism of the chemopreventive agents. Moreover, many genetically edited and some chemically-induced carcinogenesis models produce tumors that exhibit cancerous histology but are not cancers because the tumor cells are still mortal, inducer-dependent, and unable to metastasize, and thus should be used with caution in chemoprevention studies. Lastly, since mice prefer an ambient temperature of 30-32°C, it should be debated whether future mouse studies should be performed at this temperature, but not at 21-23°C that cold-stresses the animals.

MicroRNA-101 suppresses progression of lung cancer through the PTEN/AKT signaling pathway by targeting DNA methyltransferase 3A

“…Hypermethylation is responsible for the silencing of TSGs involved in tumorigenesis (19,20). DNMT3A, like other DNMT family members, is involved in tumorigenesis, differentiation and metastasis (21,22), but the correlation between DNMT3A and NSCLCs remains largely unknown. In the last ten years, miRNAs have been noted to play a significant role in the initiation and progression of NSCLCs (23,24).…”

Survival rates of homozygotic Tp53 knockout rats as a tool for preclinical assessment of cancer prevention and treatment

“…More recently, Prasad et al [22] argued that in cancer-related drug discovery, serendipity and coincidence have thus far played a much larger role than rational drug discovery. Indeed, for several reasons, experiments with cell cultures and mice are poorly predictive of clinical results with new cancer treatments [23], and even less of successful chemoprevention [24].…”

While it is not deliberate, much of today's biomedical research contains logical and technical flaws, showing a need for corrective action

“…The real situation is actually much worse, as many of the histologically malignant tumors induced in these genetically modified animals are not verifiably malignant, and not even authentically benign, and have little human relevance. This is because these tumors are the-inducer-dependent, mortal, non-autonomous, incapable of metastasizing, and curable simply by removal of the inducer or by a surgical removal 41 , 42 . Unfortunately, few publications germane to this area discourse about these unfavorable but iconic features of “cancers” induced in many animal models.…”

“…The abovementioned animal models of carcinogenesis also require a deeper rumination from another philosophical slant: Many genetically manipulated animals engender overt histologically-malignant tumors in the target organ at 100% incidence, i.e. all animals develop tumor(s), although to us their malignancy is untenable, as expounded above and before 41 , 42 . However, in many of these animal models, such as in several c-myc transgenic lines 43 - 46 , there are only one to several tumors developed in each animal in the whole lifespan, whereas billions or even trillions of other cells in the same organ do not develop to malignancy, although all these cells received the same genetic modification as those cells that evolve to the tumors.…”

“…However, this phenomenon of the-inducer-dependency of tumors was already reported by Fishcer in 1906 and confirmed by Helmholz in 1907; they, according to Davis, Vasiliev and Cheung 103 , 104 , observed that painting the ears of rabbits with Scarlet Red could induce papillomas, but the tumors regressed upon discontinuation of the painting. Since 1910s, a sheer number of studies have shown that tumors induced in animals, unless they are at very advanced stages, will regress upon withdrawal of the chemical or transgene inducers, with a small number of references given herein 41 , 105 - 127 . Moreover, a similar phenomenon of this inducer-dependency has also been reported since 1930s for tumors induced with sex steroids 128 - 135 , as we reviewed previously 40 , 41 , 136 , 137 .…”