Loss of epithelial p53 and αv integrin cooperate through Akt to induce squamous cell carcinoma yet prevent remodeling of the tumor microenvironment

Abstract

Most of the squamous cell carcinomas (SCCs) of the skin and head and neck contain p53 mutations. The presence of p53 mutations in premalignant lesions suggests that they represent early events during tumor progression and additional alterations may be required for SCC development. Here we show that co-deletion of the p53 and αv integrin genes in mouse stratified epithelia induced SCCs in 100% of the mice, more frequently and with much shorter latency than deletion of either gene alone. The SCCs that lacked p53 and αv in the epithelial tumor cells exhibited high Akt activity, lacked multiple types of infiltrating immune cells, contained a defective vasculature, and grew slower than tumors that expressed p53 or αv. These results reveal that loss of αv in epithelial cells that lack p53 promotes SCC development, but also prevents remodeling of the tumor microenvironment and delays tumor growth. We observed that Akt inactivation in SCC cells that lack p53 and αv promoted anoikis. Thus, tumors may arise in these mice as a result of the increased cell survival induced by Akt activation triggered by loss of αv and p53, and by the defective recruitment of immune cells to these tumors, which may allow immune evasion. However, the defective vasculature and lack of a supportive stroma create a restrictive microenvironment in these SCCs that slows their growth. These mechanisms may underlie the rapid onset and slow growth of SCCs that lack p53 and αv.

The integrin αv-TGFβ signaling axis is necessary for epidermal proliferation during cutaneous wound healing

“…55 Deletion of av in the mouse epidermis in the absence of p53 leads to accelerated tumor formation (potentially due to Akt activation), but subsequently, slowed tumor growth, potentially due to decreased immune cell infiltration, vascularization of the tumors, or defective keratinocyte proliferation. 11 Integrin b6 deficient mice show enhanced proliferation in hair follicles after depilation, also in a TGFb-dependent manner. 56 Some of these differences in phenotypes may be the result of the dose-dependent effects of TGFb signaling, as partial av integrin blockade may have different effects than complete genetic loss.…”

“…9,10 However, specific roles for av integrins in wound re-epithelialization are unclear. 11 av integrins activate one of their ligands-transforming growth factor b (TGFb)-which is secreted into the matrix as an inactive latent form, and contributes to wound healing. 12,13 TGFb isoforms bind to heterodimers of TGFbRI and TGFbRII, which form serine/threonine kinase receptors.…”

Focal-adhesion-independent integrin-αv regulation of FAK and c-Myc is necessary for 3D skin formation and tumor invasion

“…In mouse skin, integrin-αv deletion cooperates with p53 loss to transiently promote initial SCC formation, but ultimately results in decreased tumor growth (Savar et al, 2014). Knockout of integrin αv in mouse eyelids and conjunctiva also seems to promote SCC formation (McCarty et al, 2008).…”

“…Integrin-αv-null mice die during embryogenesis, or immediately after birth, whereas ablation of epidermal integrin αv during embryogenesis does not result in obvious morphological defects (Bader et al, 1998;Savar et al, 2014). Normal skin tissue proliferation in response to 7,12-Dimethylbenz[a]anthracene (DMBA) or 12-O-tetradecanoylphorbol-13-acetate (TPA) has not been examined in skin conditional integrin-αv-knockout mice (Savar et al, 2014).…”

“…Normal skin tissue proliferation in response to 7,12-Dimethylbenz[a]anthracene (DMBA) or 12-O-tetradecanoylphorbol-13-acetate (TPA) has not been examined in skin conditional integrin-αv-knockout mice (Savar et al, 2014). Ablation of integrin β5 or integrin β6 during embryogenesis does not lead to skin defects, indicating that these heterodimers are not necessary for epidermal development (Huang et al, 2000;Xie et al, 2012).…”