Carcinogen-Induced Skin Tumor Development Requires Leukocytic Expression of the Transcription Factor Runx3

Abstract

Carcinogen-induced skin tumorigenesis depends heavily on proinflammatory tumor-promoting processes. Here, we show that leukocytic Runx3 expression is central to the two-stage DMBA/TPA-induced skin tumorigenesis. Runx3-null mice were highly resistant to this process and concomitant ablation of Runx3 in dendritic and T cells fully recapitulated this resistance. Mechanistically, this resistance was associated with a shift in the skin cytokine milieu toward a tumor nonpermissive microenvironment. Specifically, leukocytic Runx3 loss substantially increased the antitumorigenic cytokine thymic stromal lymphopoietin (TSLP) and profoundly decreased two protumorigenic cytokines, interleukin-17a and osteopontin. Therefore, inflammation-mediated tumor promotion requires leukocytic Runx3 expression, as its loss creates a unique cytokine composition that polarizes the tumor microenvironment to a potent antitumorigenic state. Cancer Prev Res; 7(9); 913-26. Ó2014 AACR.

Runx3 at the interface of immunity, inflammation and cancer

“…For example, expression of Cxcr3 in T cells [125] and the receptor for advanced glycation end-products RAGE [126] in immune cells, but not in keratinocytes, was found to be required for sustaining TPA-induced infiltration of inflammatory cells, epidermal hyperplasia and tumor promotion. Analysis of the role of Runx3 has shown that while 100% of DMBA/TPA WT ICR mice developed multiple skin papilloma tumors, the degree of inflammation-associated epithelial hyperplasia and the frequency of papilloma-bearing mice were strongly reduced in Runx3 −/− mice [18]. Runx3 −/− mice were also highly resistant to TPA-induced tumor promotion in skin already pre-initiated by an oncogenic Ha-Ras [18].…”

“…Analysis of the role of Runx3 has shown that while 100% of DMBA/TPA WT ICR mice developed multiple skin papilloma tumors, the degree of inflammation-associated epithelial hyperplasia and the frequency of papilloma-bearing mice were strongly reduced in Runx3 −/− mice [18]. Runx3 −/− mice were also highly resistant to TPA-induced tumor promotion in skin already pre-initiated by an oncogenic Ha-Ras [18]. The reduced susceptibility of Runx3-deficient mice to skin carcinogenesis was associated with a marked reduction in TPA-recruited skin CD11b + DCs and γδT cells and with an altered cytokine milieu in their skin, which together generated an anti-tumor environment [18].…”

“…Runx3 −/− mice were also highly resistant to TPA-induced tumor promotion in skin already pre-initiated by an oncogenic Ha-Ras [18]. The reduced susceptibility of Runx3-deficient mice to skin carcinogenesis was associated with a marked reduction in TPA-recruited skin CD11b + DCs and γδT cells and with an altered cytokine milieu in their skin, which together generated an anti-tumor environment [18]. Moreover, mice in which Runx3 was specifically deleted in both DCs and T cells (using Runx3 fl/fl::CD11c-Cre::Lck-Cre mice), but not in keratinocytes (using Runx3 fl/fl::K14-Cre mice), fully simulate the resistance of Runx3 −/− mice to skin carcinogenesis [18].…”

“…The reduced susceptibility of Runx3-deficient mice to skin carcinogenesis was associated with a marked reduction in TPA-recruited skin CD11b + DCs and γδT cells and with an altered cytokine milieu in their skin, which together generated an anti-tumor environment [18]. Moreover, mice in which Runx3 was specifically deleted in both DCs and T cells (using Runx3 fl/fl::CD11c-Cre::Lck-Cre mice), but not in keratinocytes (using Runx3 fl/fl::K14-Cre mice), fully simulate the resistance of Runx3 −/− mice to skin carcinogenesis [18]. These results indicate that Runx3 −/− mice protection against inflammation-dependent skin carcinogenesis is due to loss of Runx3 activity in immune cells and not in keratinocytes (Fig.…”

“…Compelling evidence from several laboratories [6,12,[17][18][19][20][21][22][23][24][25][26][27][28][29][30] (Table 1) and the human proteome atlas portal (http: www.proteinatlas.org) demonstrating the lack of RUNX3 expression in normal GIT epithelium and other epithelial tissues has challenged the claim that RUNX3 is a TSG inactivated in GC or in other cancers. The large body of data disproving the claim that RUNX3 is a bona fide TSG and highlighting its functions in immunity and inflammation is the subject of this review.…”