Chemical Carcinogenesis Models of Cancer: Back to the Future

Abstract

Over a century has elapsed since the first demonstration that exposure to chemicals in coal tar can cause cancer in animals. These observations provided an essential causal mechanistic link between environmental chemicals and increased risk of cancer in human populations. Mouse models of chemical carcinogenesis have since led to the concept of multistage tumor development through distinct stages of initiation, promotion, and progression and identified many of the genetic and biological events involved in these processes. Recent breakthroughs in DNA sequencing have now given us tools to dissect complete tumor genome architectures and revealed that chemically induced cancers in the mouse carry a high point mutation load and mutation signatures that reflect the causative agent used for tumor induction. Chemical carcinogenesis models may therefore provide a route to identify the causes of mutation signatures found in human cancers and further inform studies of therapeutic drug resistance and responses to immunotherapy, which are dependent on mutation load and genetic heterogeneity.

Capturing the primordial Kras mutation initiating urethane carcinogenesis

“…In support of the second, a Kras allele whereby the 3ʹ end was replaced with Hras exons to encode Hras protein was found mutated in urethane-induced tumors 55 , indicating that under a Kras promoter Hras Q61L is indeed oncogenic in the lung. Whether the inability of oncogenic mutations in Hras to promote lung tumorigenesis is because the protein is less oncogenic, expressed too low, too high, combinations thereof, or for other reasons 7,24,56,57 remains to be elucidated. Nevertheless, the finding that Hras is mutated yet such mutations are not recovered in lung tumors 3 after urethane exposure is in itself an important finding, and perhaps related, of the three RAS genes, HRAS is mutated the least often in human cancers 6,7,58 .…”

Wnt Signaling Pathways in Keratinocyte Carcinomas

“…Decades ago, in order to mimic SCC development in mice, a two-stage chemical carcinogenesis protocol, involving a single application of 7,12-Dimethylbenzanthracene (DMBA) followed by a repeated treatment with 12-O-Tetradecanoylphorbol-13-acetate (TPA), was exploited in murine models. DMBA administration causes the formation of DNA adducts, and successive treatment with TPA leads to sustained hyperplasia [127,128]. It is known that treatment with DMBA/TPA creates an accumulation of mutations in several critical genes, notably in H-Ras (A182T) [129], and provokes the progression of papilloma to malignant tumor, e.g., cSCC.…”

Signaling levels mold the RAS mutation tropism of urethane

“…Focusing on lung cancer, in humans oncogenic KRAS mutations have been detected in premalignant lesions ( Kanda et al, 2012 ) as well as in multiple regions within the same tumor ( Zhang et al, 2014a ), indicative of an early origin ( Wistuba and Gazdar, 2006 ). In mice, oncogenic Kras mutations are capable of initiating tumors in carcinogen ( McCreery and Balmain, 2017 ) and genetically engineered ( Kwon and Berns, 2013 ) lung cancer models. As early driver mutations, it follows that RAS mutation tropism is a reflection of the normal cells in which the mutation first occurred.…”