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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 (CIN13), 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

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.

pathologically classified as squamous cell carcinoma. To begin to uncover molecular and genetic changes associated with these histological transitions, David Gius, M.D., Ph.D., Head of the Molecular Radiation Oncology Section in CCRs Radiation Oncology Branch, and other CCR researchers teamed up with scientists from Washington University School of Medicine. The results of their efforts were recently published in Cancer Research.

Dr. 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, including CIN1, CIN2, CIN3, and cervical squamous cell carcinoma. 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.

RNA from the microdissected samples was used to perform gene expression profiling. Gene expression changes due to individual variation were filtered out using statistical tools, and additional samples were used to validate initial results. The subsequent gene expression patternsor genomic signaturesgenerated 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.

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 IFN IFN

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, gene activities change. In transition toward the CIN 1 stage, gene activities involved in increasing cell proliferation and suppressing an immune response are detectable. Later, as the cervical cell moves from a CIN 1 to a CIN 2 stage, gene activities involved in corrupting the normal stromal-epithelial environment and encouraging angiogenesis are evident. Finally, gene activities involved in invasion are present in the CIN 3 stage.

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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-

Jak1

CDKN2A CDK4
Cyclin D1

ACAA1
CENPF CENPE KIF23 9-cis RA PPAR PPAR ligand RXR

NOMO2 Smad 2/3 DSG3 Pro-Apoptosis Genes

MMP3 MMP14 NF-B

Apoptosis

E6 E7 3

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 MSH APOPTOSIS SUMO1 MITF HIF1 HIF1

HINT1

Identifying Molecular Culprits of Cervical Cancer Progression 

The model consists of three distinct functional genomic signatures. The first signature was associated with the transition from early viral infection to CIN1. This histological change coincided with altered expression of genes associated with cellular proliferation and suppression of the immune system. The environment created by this genomic signature may allow HPV to replicate without being detected and destroyed by the immune system. Tissue that had progressed to CIN2 demonstrated a genomic signature favoring growth of new blood vessels. Interestingly, these changes occur in both epithelial and stromal cells, suggesting that communication between different cell types may be important for blood vessel expansion during CIN2.

CIN3 and squamous cell carcinoma cervical tissue exhibited a pro-invasive genomic signature, including changes in cell adhesion proteins and enzymes involved in extracellular matrix remodeling in both epithelial and stromal cells. Based on these results, the research team hypothesized that the predominant cellular stresses present at the CIN3 transition may be due to cellular overcrowding. In addition, 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. 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 genes and pathways identified may also contribute to the discovery of biomarkers useful for cervical cancer screening.

Reference
Gius D, Funk MC, Chuang EY, Feng S, Huettner PC, Nguyen L, Bradbury CM, Mishra M, Gao S, Buttin BM, Cohn DE, Powell MA, Horowitz NS, Whitcomb BP, Rader JS. Profiling microdissected epithelium and stroma to model genomic signatures for cervical carcinogenesis accommodating for covariates. Cancer Res 67: 711323, 2007.

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Identifying Molecular Culprits of Cervical Cancer Progression 

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