Loss of TGFbeta signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia.
Although TGFbeta is a potent inhibitor of proliferation, epithelia lacking the essential receptor (TbetaRII) for TGFbeta signaling display normal tissue homeostasis. By studying asymptomatic TbetaRII-deficient stratified epithelia, we show that tissue homeostasis is maintained by balancing hyperproliferation with elevated apoptosis. Moreover, rectal and genital epithelia, which are naturally proliferative, develop spontaneous squamous cell carcinomas with age when TbetaRII is absent. This progression is associated with a reduction in apoptosis and can be accelerated in phenotypically normal epidermis by oncogenic mutations in Ras. We show that TbetaRII deficiency leads to enhanced keratinocyte motility and integrin-FAK-Src signaling. Together, these mechanisms provide a molecular framework to account for many of the characteristics of TbetaRII-deficient invasive SQCCs.
Guasch
Géraldine
G
Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021, USA.
Schober
Markus
M
Pasolli
H Amalia
HA
Conn
Emily Belmont
EB
Polak
Lisa
L
Fuchs
Elaine
E
D000818:Animals; D001005:Anus Neoplasms / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D016023:Integrins / Q000378:metabolism; D053547:Keratin-14 / Q000235:genetics; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009361:Neoplasm Invasiveness; D010212:Papilloma / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014565:Urogenital Neoplasms / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D016023:Integrins; C507540:KRT14 protein, human; D053547:Keratin-14; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018631:ras Proteins