Inhibition of HGF/MET signaling decreases overall tumor burden and blocks malignant conversion in Tpl2-related skin cancer

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.

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

“…Elsewhere, celecoxib was reported to inhibit cancer stem cell properties of colorectal cancer (CRC) cells by targeting c-Met activity, raising the possibility that celecoxib anti-tumor effect in TPL2 -/- mice was as a result of suppressed c-Met activity 103 . Consistently, squamous cell carcinomas (SCCs) and keratinocytes from TPL2 -/- mice showed increased HGF expression and c-Met activation that contributed to increased stem cell acquisition and metastasis 90 . However, pharmacological inhibition of c-Met results in a significant reduction in tumor burden in TPL2 -/- mice further implicating c-Met activation in tumor progression in TPL2 deficient mice 89 , 90 .…”

“…Consistently, squamous cell carcinomas (SCCs) and keratinocytes from TPL2 -/- mice showed increased HGF expression and c-Met activation that contributed to increased stem cell acquisition and metastasis 90 . However, pharmacological inhibition of c-Met results in a significant reduction in tumor burden in TPL2 -/- mice further implicating c-Met activation in tumor progression in TPL2 deficient mice 89 , 90 . Loss of TPL2 in IMFs also resulted in the increased production of HGF and tumor susceptibility in TPL2 -/- mice 89 .…”

“…Despite its essential role in the production of inflammatory factors, TPL2 loss in CAFs was reported to promote NF-κB activation, inflammation and tumorigenesis 88 . Consistently, cell-specific TPL2 ablation in intestinal subepithelial myofibroblasts (IMFs) and keratinocytes resulted in increased hepatocyte growth factor (HGF, also known as scatter factor) production that was proposed to propagate increased tumor burden in TPL2 deficient mice 89 , 90 . HGF released by fibroblast exerts its tumorigenic function by activating the tyrosine receptor, c-Met, on tumor cells, which in turn activates various growth factors and signaling pathways involved in cancer cell proliferation, apoptosis resistance, invasion, angiogenesis and drug resistance 88 - 90 .…”

“…Together, these studies implicate the IKKβ/RelA signaling in the regulation of HGF production. Assuming that suppressed RelA signaling contributes to HGF production in the absence of TPL2, we propose that altered RelA signaling is the common denominator responsible for the phenotypic similarities in both IKKβ-deficient and TPL2-deficient CAFs 89 , 90 , 104 .…”

Molecular genetics of cutaneous squamous cell carcinoma: perspective for treatment strategies

“…Furthermore, MET signalling might initiate squamous carcinogenesis through activation of EGFR in cultured keratinocytes from transgenic mice . Recently, Bonan et al . supported the cooperation of MET and EGFR in skin carcinogenesis showing that treatment with capmatinib, a selective MET inhibitor, might prevent the HGF‐stimulated upregulation of EGFR protein highlighting the potential of MET as therapeutic target for cSCC.…”