Tumor formation initiated by nondividing epidermal cells via an inflammatory infiltrate.
In mammalian epidermis, integrin expression is normally confined to the basal proliferative layer that contains stem cells. However, in epidermal hyperproliferative disorders and tumors, integrins are also expressed by suprabasal cells, with concomitant up-regulation of Erk mitogen-activated protein kinase (MAPK) signaling. In transgenic mice, expression of activated MAPK kinase 1 (MEK1) in the suprabasal, nondividing, differentiated cell layers (InvEE transgenics) results in epidermal hyperproliferation and skin inflammation. We now demonstrate that wounding induces benign tumors (papillomas and keratoacanthomas) in InvEE mice. By generating chimeras between InvEE mice and mice that lack the MEK1 transgene, we demonstrate that differentiating, nondividing cells that express MEK1 stimulate adjacent transgene-negative cells to divide and become incorporated into the tumor mass. Dexamethasone treatment inhibits tumor formation, suggesting that inflammation is involved. InvEE skin and tumors express high levels of IL1α; treatment with an IL1 receptor antagonist delays tumor onset and reduces incidence. Depletion of γδ T cells and macrophages also reduces tumor incidence. Because a hallmark of cancer is uncontrolled proliferation, it is widely assumed that tumors arise only from dividing cells. In contrast, our studies show that differentiated epidermal cells can initiate tumor formation without reacquiring the ability to divide and that they do so by triggering an inflammatory infiltrate.
Cancer Research UK Cambridge Research Institute, Cambridge CB2 0RE, United Kingdom.
Esther N
EN
Arwert
Rohit
R
Lal
Sven
S
Quist
Ian
I
Rosewell
Nico
N
van Rooijen
Fiona M
FM
Watt
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004817:Epidermis / Q000187:drug effects / Q000473:pathology*; D007249:Inflammation / Q000473:pathology*; D053582:Interleukin-1alpha / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000473:pathology*; D010212:Papilloma / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000473:pathology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D019076:Transgenes; D014945:Wound Healing / Q000187:drug effects
D053582:Interleukin-1alpha; D016692:Receptors, Antigen, T-Cell, gamma-delta