TY - JOUR
T1 - Loss of Trop2 promotes carcinogenesis and features of epithelial to mesenchymal transition in squamous cell carcinoma
AU - Wang, Jianbo
AU - Zhang, Kaihua
AU - Grabowska, Dorota
AU - Li, Aimin
AU - Dong, Yiyu
AU - Day, Ryan
AU - Humphrey, Peter
AU - Lewis, James
AU - Kladney, Raleigh D.
AU - Arbeit, Jeffrey M.
AU - Weber, Jason D.
AU - Chung, Christine H.
AU - Michel, Loren S.
PY - 2011/12
Y1 - 2011/12
N2 - Trop2, an oncogenic cell surface protein under investigation as a therapeutic target, is commonly overexpressed in several epithelial tumor types yet its function in tumor biology remains relatively unexplored. To investigate the role of Trop2 in epithelial carcinogenesis, we generated Trop2 -/- mice, which are viable and possess a normal lifespan. Contrary to expectations, Trop2 loss fails to suppress keratinocyte transformation. Instead, rastransformed Trop2 -/- keratinocytes preferentially pass through an epithelial to mesenchymal transition (EMT) and form tumors with spindle cell histology. Furthermore, Trop2 loss renders Arf-null mice susceptible to the formation of biphasic sarcomatoid carcinomas containing both squamous and spindle cell components upon carcinogen exposure in an otherwise skin cancer-resistant strain (C57BL/6). Immortalized keratinocytes derived from Trop2 -/- Arf -/- mice exhibit enhanced proliferative and migratory capacity as well as increased activation of mitogen-activated protein kinase and Src prior to transformation. The clinical relevance of these findings was supported by studying the molecular epidemiology of Trop2 in primary head and neck squamous cell carcinomas. This analysis revealed that Trop2 mRNA levels are decreased in a subset of tumors with features of EMT, and total loss of Trop2 protein expression is observed in the spindle cell component of sarcomatoid carcinomas. Therefore, while previous studies have emphasized the potential importance of Trop2 gain of function, these results uncover a role for Trop2 loss in tumorigenesis and the mesenchymal transdifferentiation observed in a subset of squamous cell carcinomas.
AB - Trop2, an oncogenic cell surface protein under investigation as a therapeutic target, is commonly overexpressed in several epithelial tumor types yet its function in tumor biology remains relatively unexplored. To investigate the role of Trop2 in epithelial carcinogenesis, we generated Trop2 -/- mice, which are viable and possess a normal lifespan. Contrary to expectations, Trop2 loss fails to suppress keratinocyte transformation. Instead, rastransformed Trop2 -/- keratinocytes preferentially pass through an epithelial to mesenchymal transition (EMT) and form tumors with spindle cell histology. Furthermore, Trop2 loss renders Arf-null mice susceptible to the formation of biphasic sarcomatoid carcinomas containing both squamous and spindle cell components upon carcinogen exposure in an otherwise skin cancer-resistant strain (C57BL/6). Immortalized keratinocytes derived from Trop2 -/- Arf -/- mice exhibit enhanced proliferative and migratory capacity as well as increased activation of mitogen-activated protein kinase and Src prior to transformation. The clinical relevance of these findings was supported by studying the molecular epidemiology of Trop2 in primary head and neck squamous cell carcinomas. This analysis revealed that Trop2 mRNA levels are decreased in a subset of tumors with features of EMT, and total loss of Trop2 protein expression is observed in the spindle cell component of sarcomatoid carcinomas. Therefore, while previous studies have emphasized the potential importance of Trop2 gain of function, these results uncover a role for Trop2 loss in tumorigenesis and the mesenchymal transdifferentiation observed in a subset of squamous cell carcinomas.
UR - http://www.scopus.com/inward/record.url?scp=84055216936&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-11-0241
DO - 10.1158/1541-7786.MCR-11-0241
M3 - Article
C2 - 21970857
AN - SCOPUS:84055216936
SN - 1541-7786
VL - 9
SP - 1686
EP - 1695
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 12
ER -