Abstract
Tumor progression locus 2 (Tpl2) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family of serine/threonine kinases. Deletion of the Tpl2 gene is associated with a significantly higher number of papillomas and cutaneous squamous cell carcinomas (cSCCs). Overexpression of hepatocyte growth factor (HGF) and its receptor MET is abundant in cSCC and can lead to increased proliferation, migration, invasion or resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. The aim of this study was to address whether the increased tumor burden in Tpl2−/− mice is due to aberrant HGF/MET signaling. C57Bl/6 wild type (WT) and Tpl2−/− mice were subjected to a two-stage chemical carcinogenesis protocol for one year. At the time of promotion half of the mice received 44 mg/kg capmatinib (INC 280), a pharmacological inihibitor of MET, in their diet. Tpl2−/− mice had signficantly higher tumor incidence and overall tumor burden compared to WT mice. Further, carcinogen-intiated Tpl2−/− mice could bypass the need for promotion, as 89% of Tpl2−/− mice given only DMBA developed papillomas. v-rasHa -transduced keratinocytes and SCCs from Tpl2−/− mice revealed an upregulation in HGF and p-MET signaling compared to WT animals. Long-term capmatinib treatment had no adverse effects in mice and capmatinib-fed Tpl2−/− mice had a 60% reduction in overall tumor burden. Further, no tumors from Tpl2−/− mice fed capmatinib underwent malignant conversion. In summary targeting MET may be a potential new strategy to combat cutaneous squamous cell carcinomas that result from dysregulation in MAPK signaling.
Highlights
Cutaneous squamous cell carcinoma is the second most common form of cancer in the United States and has the highest mortality of all non-melanoma skin cancers[1]
V-rasHa-transduced wild type (WT) keratinocytes grown in Tumor progression locus 2 (Tpl2) −/− fibroblast conditioned media had a 71% increase in cell proliferation compared to v-rasHa-transduced WT keratinocytes grown in normal supplemented media. v-rasHatransduced Tpl2 −/− keratinocytes grown in Tpl2 −/− fibroblast conditioned media had a 32% increase in cell proliferation compared to v-rasHa-transduced Tpl2 −/−
83% of the Tpl2 −/− cultures developed a single focus in response to signals from WT fibroblasts (Table 1, Fig. 1b, “v”, p < 0.005) and 100% of the Tpl2 −/− keratinocyte cultures grown in conditioned media from Tpl2 −/− fibroblasts developed at least one focus, with one culture developing two foci (Table 1, Fig. 1b “vi”, p < 0.00001)
Summary
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of cancer in the United States and has the highest mortality of all non-melanoma skin cancers[1]. Skin carcinogenesis is a complex, multistep process and in vivo mouse models remain among the best established tools to study skin cancer development and progression[2]. Tumors begin to develop within a few months, depending on mouse strain, with a small percentage progressing to invasive SCC2. Tumor progression locus 2 (Tpl2), called MAP3K8, is a member of the mitogen-activated protein kinase (MAPK) family. Tpl[2] has a divergent role in cancer, working as an oncogene or tumor suppressor gene depending on context or tissue in which the signal is aberrantly altered[3]. Increased Tpl[2] activity has been reported in multiple cancer types, including breast, colon and gastric cancer, nasopharyngeal carcinoma, thymoma, lymphoma, and keratoacanthoma[4,5,6,7,8,9].
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