Inducible Cutaneous Inflammation Reveals a Protumorigenic Role for Keratinocyte CXCR2 in Skin Carcinogenesis

Abstract

Transgenic mice that overexpress PKCA in the epidermis (K5-PKCA mice) exhibit acute CXCR2-mediated intraepidermal neutrophilic inflammation and a strong epidermal hyperplasia in response to application of 12-O-tetradecanoylphorbol-13-acetate (TPA). We now show that hyperplasia is independent of infiltrating neutrophils. Furthermore, when K5-PKCA mice were initiated with 7,12-dimethylbenz(a)annthracene (DMBA) and promoted with a low dose of TPA, 58% of K5-PKCA mice developed skin papillomas that progressed to carcinoma, whereas wild-type mice did not develop tumors. We confirmed that CXCR2 is expressed by keratinocytes and showed that transformation by oncogenic ras (a hallmark of DMBA initiation) or TPA exposure induced all CXCR2 ligands. Ras induction of CXCR2 ligands was mediated by autocrine activation of epidermal growth factor receptor and nuclear factor-KB, and potentiated by PKCA. Oncogenic ras also induced CXCR2 ligands in keratinocytes genetically ablated for CXCR2. However, ras transformed CXCR2 null keratinocytes formed only small skin tumors in orthotopic skin grafts to CXCR2 intact hosts, whereas transformed wild-type keratinocytes produced large tumors. In vitro, CXCR2 was essential for CXCR2 ligand-stimulated migration of ras-transformed keratinocytes and for ligand activation of the extracellular signal-regulated kinase (ERK) and Akt pathways. Both migration and activation of ERK and Akt were restored by CXCR2 reconstitution of CXCR2 null keratinocytes. Thus, activation of CXCR2 on ras-transformed keratinocytes has both promigratory and protumorigenic functions. The upregulation of CXCR2 ligands after initiation by oncogenic ras and promotion with TPA in the mouse skin model provides a mechanism to stimulate migration by both autocrine and paracrine pathways and contribute to tumor development.

Influence of interleukin-8 (IL-8) and IL-8 receptors on the migration of human keratinocytes, the role of PLC-γ and potential clinical implications

“…CXC chemokine-induced chemotaxis involves a number of intracellular signalling pathways, classically the JAK, Src/PI3K, FAK and PLC pathways (27)(28)(29)(30). The present study clearly demonstrates that the IL-8-induced migration of HaCaT cells (chemokinesis) critically requires the PLC-γ pathway, in that the PLC-γ inhibitor suppressed IL-8-induced migration and completely blocked the action of IL-8.…”

“…Of course, IL-8 is not at all a clear wound healer without concerns. It has been shown that IL-8RB may mediate skin carcinogenesis when overexpressed or repeatedly induced (30).…”

Ets1 blocks terminal differentiation of keratinocytes and induces expression of matrix metalloproteases and innate immune mediators

“…proliferation and migration (Cataisson et al, 2009;Coppe et al, 2008;Coussens et al, 1999;Takahashi et al, 2010).…”

Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis

“…Its function on transformed cells is context dependent. For example, CXCR2 is required for the optimal growth of ras-transformed keratinocytes in vivo (17) and has been shown to stimulate tumor cell growth, survival, and motility in several model systems (18)(19)(20). In contrast, induction of CXCR2 and its ligands by oncogenic K-ras reinforces senescence in vitro (21), predicting a role in tumor suppression in vivo.…”