Correlation of CXCL12 expression and FoxP3+ cell infiltration with human papillomavirus infection and clinicopathological progression of cervical cancer.
Human cervical cancer is an immunogenic tumor with a defined pattern of histopathological and clinical progression. Tumor-infiltrating T cells contribute to immune control of this tumor; however, cervical cancer dysregulates this immune response both through its association with human papillomavirus (HPV) infection and by producing cytokines and chemokines. Animal tumor models have revealed associations between overproduction of the chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) and dysregulation of tumor-specific immunity. We therefore proposed that CXCL12 expression by cervical precancerous and cancerous lesions correlates with histopathological progression, loss of immune control of the tumor, and HPV infection. We found a significant association between cancer stage and CXCL12 expression for squamous and glandular lesions as well as with the HPV16+ (high-risk) status of the neoplastic lesions. Cancer progression was correlated with increasing levels of FoxP3 T-cell infiltration in the tumor. FoxP3 and CXCL12 expression significantly correlated for squamous and glandular neoplastic lesions. These observations were supported by enzyme-linked immunosorbent assay and Western blotting. In addition, we demonstrated CXCL12 expression by dyskaryotic cells in ThinPrep cervical smears. This study robustly links increased CXCL12 expression and FoxP3(+)-cell infiltration to HPV infection and progression of cervical cancer. It supports the detection of CXCL12 in cervical smears and biopsies as an additional biomarker for this disease.
Jaafar
Fatimah
F
Department of Histopathology and Cytology, Imperial College, Hammersmith Hospital, London, United Kingdom.
Righi
Elda
E
Lindstrom
Victoria
V
Linton
Christine
C
Nohadani
Mahrokh
M
Van Noorden
Susan
S
Lloyd
Tyler
T
Poznansky
Joshua
J
Stamp
Gordon
G
Dina
Roberto
R
Coleman
Dulcie V
DV
Poznansky
Mark C
MC
D000469:Alkaline Phosphatase / Q000378:metabolism; D015153:Blotting, Western; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D027383:Papillomaviridae / Q000502:physiology; D030361:Papillomavirus Infections / Q000150:complications* / Q000276:immunology*; D009195:Peroxidase / Q000378:metabolism; D046888:Tissue Array Analysis; D002583:Uterine Cervical Neoplasms / Q000150:complications / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D014626:Vaginal Smears
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D054377:Chemokine CXCL12; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D009195:Peroxidase; D000469:Alkaline Phosphatase