In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 11 ( 2021-11-4), p. e0259245-
Abstract:
Anal squamous cell carcinoma (SCC) will be diagnosed in an estimated 9,080 adults in the United States this year, and rates have been rising over the last several decades. Most people that develop anal SCC have associated human papillomavirus (HPV) infection (~85–95%), with approximately 5–15% of anal SCC cases occurring in HPV-negative patients from unknown etiology. This study identified and characterized the Kras -driven, female sex hormone-dependent development of anal squamous cell carcinoma (SCC) in the LSL-Kras G12D ; Pdx1-Cre (KC) mouse model that is not dependent on papillomavirus infection. One hundred percent of female KC mice develop anal SCC, while no male KC mice develop tumors. Both male and female KC anal tissue express Pdx1 and Cre-recombinase mRNA, and the activated mutant Kras G12D gene. Although the driver gene mutation Kras G12D is present in anus of both sexes, only female KC mice develop Kras -mutant induced anal SCC. To understand the sex-dependent differences, KC male mice were castrated and KC female mice were ovariectomized. Castrated KC males displayed an unchanged phenotype with no anal tumor formation. In contrast, ovariectomized KC females demonstrated a marked reduction in anal SCC development, with only 15% developing anal SCC. Finally, exogenous administration of estrogen rescued the tumor development in ovariectomized KC female mice and induced tumor development in castrated KC males. These results confirm that the anal SCC is estrogen mediated. The delineation of the role of female sex hormones in mediating mutant Kras to drive anal SCC pathogenesis highlights a subtype of anal SCC that is independent of papillomavirus infection. These findings may have clinical applicability for the papillomavirus-negative subset of anal SCC patients that typically respond poorly to standard of care chemoradiation.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0259245
DOI:
10.1371/journal.pone.0259245.g001
DOI:
10.1371/journal.pone.0259245.g002
DOI:
10.1371/journal.pone.0259245.g003
DOI:
10.1371/journal.pone.0259245.g004
DOI:
10.1371/journal.pone.0259245.g005
DOI:
10.1371/journal.pone.0259245.g006
DOI:
10.1371/journal.pone.0259245.g007
DOI:
10.1371/journal.pone.0259245.g008
DOI:
10.1371/journal.pone.0259245.g009
DOI:
10.1371/journal.pone.0259245.t001
DOI:
10.1371/journal.pone.0259245.t002
DOI:
10.1371/journal.pone.0259245.t003
DOI:
10.1371/journal.pone.0259245.s001
DOI:
10.1371/journal.pone.0259245.s002
DOI:
10.1371/journal.pone.0259245.s003
DOI:
10.1371/journal.pone.0259245.s004
DOI:
10.1371/journal.pone.0259245.s005
DOI:
10.1371/journal.pone.0259245.s006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
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