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lesions will progress to cancer. Identification of these factors would be facilitated by a deeper understanding of the cellular and molecular changes that accompany progression to malignancy. In addition, knowledge of which women are at greatest risk for disease progression would be a significant clinical advancement in the management of patients with premalignant cervical lesions. The histological changes that occur as cervical tissue progresses from normal to cancerous have been well characterized. Preinvasive lesions are called cervical intraepithelial neoplasias (CINs). There are three CIN grades (CIN1–3), with CIN3 being the most advanced. Once the HPV-containing epithelial cells invade the basement membrane, the lesions become malignant and are
Pro-invasive genomic signature

Identifying Molecular Culprits of Cervical Cancer Progression

H

uman papillomavirus (HPV) DNA is found in 99.7% of invasive cervical carcinomas, providing strong evidence that the virus is a causative agent in the development of this disease. However, most women who become infected with HPV do not develop invasive cervical lesions, indicating that additional exogenous or genetic factors may determine whether HPV preclinical

Proliferative/ Pro-angiogenic immune suppression stromal-epithelial genomic signature genomic signature CIN1 Normal Very mild/ mild dysplasia CIN2 Moderate dysplasia Severe dysplasia

CIN3 In situ carcinoma

SCCA Invasive carcinoma

Dividing cells in basal layer

Dr. Gius and his colleagues used laser capture microdissection to analyze the gene changes that occur in individual cervical cells and the adjacent stromal cells. The researchers analyzed several precancerous stages as well as squamous cell carcinoma (SCCA) from patients’ biopsy samples. See gene changes in next figure.

gene activities involved in increasing cell proliferation and suppressing an immune response are detectable. To begin to uncover molecular and genetic changes associated with these histological transitions. In transition toward the CIN 1 stage. gene activities change. Ph. Finally. gene activities involved in corrupting the normal stromal-epithelial environment and encouraging angiogenesis are evident. including CIN1.. Gius and colleagues collected normal cervical tissue from healthy women as well as normal and abnormal cervical tissue from women with different grades of cervical disease. and additional samples were used to validate initial results. The results of their efforts were recently published in Cancer Research. RNA from the microdissected samples was used to perform gene expression profiling. M. Gene expression changes due to individual variation were filtered out using statistical tools. Later.D. and other CCR researchers teamed up with scientists from Washington University School of Medicine. They then used a technique called laser capture microdissection to separately collect epithelial and stromal cells from these tissues. this approach allowed them to pinpoint changes occurring within different tissue microenvironments. Dr. David Gius. The subsequent gene expression patterns—or genomic signatures—generated for both epithelial and stromal cells along the continuum of cervical cancer progression were used to create the first genomically based model of cervical carcinogenesis.D. Head of the Molecular Radiation Oncology Section in CCR’s Radiation Oncology Branch.. CIN3. Proliferative/immune suppression genomic signature CIN 1 P2RX7 EMP1 Inhibition Anoikis IFN Pro-angiogenic stromalepithelial genomic signature CIN 2 P2RX7 EMP1 Pro-invasive genomic signature CIN 3 SCCA Loss of contact with BM results in Anoikis IFNα IFNα IL1RN PRO-MMP2 MMP14 IL1 Microvesicle Bleb IL1RN Nodal MMP2 IFNAR1 IFNAR2 Tyk2 STAT1 ITGAV As a cervical cancer cell moves toward a cancerous phenotype. CIN2. as the cervical cell moves from a CIN 1 to a CIN 2 stage.pathologically classified as squamous cell carcinoma. gene activities involved in invasion are present in the CIN 3 stage. and cervical squamous cell carcinoma. in the JOURNALS 2-3 mm depth 2-3 mm depth IFNAR1 IFNAR2 STAT2 ILR1 Jak1 CELL DEATH Peroxisome ALK7 Smad 2/3 CDK4 Cyclin D1 E6 Virion Assembly HPV Components STAT 1/2 Tyk2 Apoptosis Rb E7 E2F ACAA1 CDKN2A E2F Rb E2F Rb E2F KAL1 Smad 2/3 VEGF FGF2 TWEAK TNFRSF12A NF-κβ Jak1 CDKN2A CDK4 Cyclin D1 ACAA1 CENPF CENPE KIF23 9-cis RA PPARα PPARα ligand RXR NOMO2 Smad 2/3 DSG3 Pro-Apoptosis Genes MMP3 MMP14 NF-κB Apoptosis E6 E7 β3 Rb E2F Cell Cycle Modified Desmosome MAST CELL PROLIFERATION VEGF FGF2 VEGF HSPG KAL1 FGF2 FGFR1 MMP3 DSG3 Modified Desmosome SWI/SNF complex SMARCA4 BRWD1 MMP2 MAP2K7 POMC mMCP4 HSPG ANGIOGENESIS TBX19 FGFR1 MC1R αMSH APOPTOSIS SUMO1 MITF HIF1α HIF1α HINT1 Identifying Molecular Culprits of Cervical Cancer Progression  .

Feng S. Mishra M. Expansion and modification of this genomically based model for cervical transformation through additional re- search should help illuminate factors that facilitate progression from HPV infection to cancer.The model consists of three distinct functional genomic signatures. suggesting that communication between different cell types may be important for blood vessel expansion during CIN2. Cancer Res 67: 7113–23. The first signature was associated with the transition from early viral infection to CIN1. Tissue that had progressed to CIN2 demonstrated a genomic signature favoring growth of new blood vessels. Powell MA. Gao S. Whitcomb BP. Chuang EY. Rader JS. Reference Gius D. Buttin BM. these changes occur in both epithelial and stromal cells. Horowitz NS. Interestingly. in the JOURNALS Identifying Molecular Culprits of Cervical Cancer Progression  . Nguyen L. Funk MC. Huettner PC. the activation of pro-invasive genes may be critical to invasion through the basement membrane and the transition from a premalignant to malignant cervical cancer. Bradbury CM. CIN3 and squamous cell carcinoma cervical tissue exhibited a pro-invasive genomic signature. In addition. including changes in cell adhesion proteins and enzymes involved in extracellular matrix remodeling in both epithelial and stromal cells. the research team hypothesized that the predominant cellular stresses present at the CIN3 transition may be due to cellular overcrowding. This histological change coincided with altered expression of genes associated with cellular proliferation and suppression of the immune system. Cohn DE. Based on these results. Profiling microdissected epithelium and stroma to model genomic signatures for cervical carcinogenesis accommodating for covariates. 2007. The environment created by this genomic signature may allow HPV to replicate without being detected and destroyed by the immune system. The genes and pathways identified may also contribute to the discovery of biomarkers useful for cervical cancer screening.

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