Abstract
The establishment of a proangiogenic phenotype and epithelial-to-mesenchymal transition (EMT) are considered as critical events that promote the induction of invasive growth in epithelial tumors, and stimulation of lymphangiogenesis is believed to confer the capacity for early dissemination to cancer cells. Recent research has revealed substantial interdependence between these processes at the molecular level as they rely on common signaling networks. Of great interest are the molecular mechanisms of (lymph-)angiogenesis and EMT associated with the earliest stages of transition from intraepithelial development to invasive growth, as they could provide the source of potentially valuable tools for targeting tumor metastasis. However, in the case of early-stage cervical cancer, the players of (lymph-)angiogenesis and EMT processes still remain substantially uncharacterized. In this study, we used RNA sequencing to compare transcriptomes of HPV(+) preinvasive neoplastic lesions and early-stage invasive carcinoma of the cervix and to identify (lymph-)angiogenesis- and EMT-related genes and pathways that may underlie early acquisition of invasive phenotype and metastatic properties by cervical cancer cells. Second, we applied flow cytometric analysis to evaluate the expression of three key lymphangiogenesis/EMT markers (VEGFR3, MET, and SLUG) in epithelial cells derived from enzymatically treated tissue specimens. Overall, among 201 differentially expressed genes, a considerable number of (lymph-)angiogenesis and EMT regulatory factors were identified, including genes encoding cytokines, growth factor receptors, transcription factors, and adhesion molecules. Pathway analysis confirmed enrichment for angiogenesis, epithelial differentiation, and cell guidance pathways at transition from intraepithelial neoplasia to invasive carcinoma and suggested immune-regulatory/inflammatory pathways to be implicated in initiation of invasive growth of cervical cancer. Flow cytometry showed cell phenotype-specific expression pattern for VEGFR3, MET, and SLUG and revealed correlation with the amount of tumor-infiltrating lymphocytes at the early stages of cervical cancer progression. Taken together, these results extend our understanding of driving forces of angiogenesis and metastasis in HPV-associated cervical cancer and may be useful for developing new treatments.
Highlights
The establishment of a proangiogenic phenotype and epithelial-to-mesenchymal transition (EMT) are presently considered as critical events that promote the induction of invasive growth in epithelial tumors, and stimulation of lymphangiogenesis is believed to confer the capacity for early metastatic dissemination to cancer cells [1]
To compare the transcriptomes of the two consecutive stages of cervical cancer progression corresponding to different phenotypic states—pre-invasive cancer and early invasive cancer—RNA sequencing was performed on a panel of samples comprising human papillomavirus (HPV)(+) cervical intraepithelial neoplasia grade 3 and early invasive squamous cell carcinoma at FIGO IA1-IIB stages, plus morphologically normal epithelium (n = 1) (Table 1)
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Summary
The establishment of a proangiogenic phenotype and epithelial-to-mesenchymal transition (EMT) are presently considered as critical events that promote the induction of invasive growth in epithelial tumors, and stimulation of lymphangiogenesis is believed to confer the capacity for early metastatic dissemination to cancer cells [1]. The ability of many molecular players that control the mechanisms of tumor-associated (lymph-)angiogenesis and EMT to compensate for each other’s functions enables their extremely high plasticity This can apparently explain the fact that anti-angiogenic (anti-VEGF/VEGFR) therapy, despite its suppressive effect on primary tumor growth, may result in promotion of metastatic spread via compensatory upregulation of genes mediating EMT and lymphangiogenesis. Simultaneous blockade of the lymphangiogenic/EMT regulators inhibits migration capacity of cancer cells [2,3], highlighting the importance of comprehensive consideration of triggering mechanisms of invasion and metastasis In this regard, of great interest are the (lymph-)angiogenesis and EMT-governing molecular factors and pathways associated with transition of intraepithelial lesion to invasive behavior [4], the earliest stages defined, according to morphological criteria, as carcinoma in situ (CIS) and carcinoma “with minimal stromal invasion”, or microinvasive cancer [5]. The potential of Next-Generation Sequencing-based techniques such as RNA sequencing (RNA-Seq) applied to different transitional states in the early phases of cancer development lies in the opportunity to get a better and more comprehensive insight into advanced metastatic cancer [4]
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