The feasibility of 18F-FDG PET/CT for predicting pathologic risk status in early-stage uterine cervical squamous cancer

Background Postoperative pathologic risk factors (PRFs) could increase the recurrence rate in early-stage uterine cervical squamous cancer (ECSC). Our study intended to explore the efficiency of 18F-FDG PET/CT for assessing the pathologic risk status (PRS) in ECSC patients. Methods This retrospective study was performed in 240 ECSC patients with stage IA2-IIA2 (FIGO 2009), who underwent preoperative PET/CT scans and subsequent radical surgery between January 2010 and July 2015. Intermediate-risk (tumour diameter ≥ 4 cm, stromal invasion depth ≥ 1/2, lymphovascular space invasion (LVSI)), and high-risk factors (parametria involvement, positive surgery margin, pelvic lymph node metastasis) were confirmed by postoperative pathology. Patients with none of these PRFs were at a low risk for relapse. One of these PRFs was defined as positive risk. The relationship between each PRF and 18F-FDG uptake was analysed by t-test. Chi-square tests and logistic regression analyses were used to determine the efficiency of PET/CT parameters for assessing the PRS. The area under the curve (AUC) was used as an indicator for predictive efficiency. Results Patients with higher SUVmax (p < 0.001), MTV (p < 0.001) and TLG (p < 0.001) had larger tumour sizes and deeper stromal invasion. Further multivariate analyses showed SUVmax and TLG were independent predictors for positive- and intermediate-risk status. In high-risk group, MTV and TLG were associated with pelvic lymph node metastasis and parametria involvement. However, only MTV was a significant indicator. Conclusions Preoperative 18F-FDG PET/CT had an independent predictive value for PRS in ECSC.

Immune negative regulator TIPE2 inhibits cervical squamous cancer progression through Erk1/2 signaling

Tumor necrosis factor (TNF)-α-induced protein-8-like 2, or TIPE2, is a newly found immune negative regulatory molecule. This study further investigated the role of TIPE2 on proliferation and invasion of cervical squamous cancer cells. Expression of TIPE2 was compared in cervical squamous cancer tissues and adjacent normal tissues by Western blot and immunohistochemistry (IHC). Cervical squamous cancer cell lines, SiHa and C33A, were transfected with recombinant plasmid encoding TIPE2 and tested for cytologic characteristics. The impact of TIPE2 on phosphorylation of extracellular signal-regulated kinase (Erk) signaling pathway was also tested by Western blot analysis of key factors. TIPE2 expression was higher in cervical cancer tissues than that in normal tissue. IHC score of tumor tissue was negatively associated with lymphatic metastasis. Over expression of TIPE2 effectively inhibited the proliferation of cervical cancer cells. Wound healing and transwell assay showed that over expression of TIPE2 suppressed cell migration and invasion in vitro. Meanwhile, phosphorylation of Erk1/2 and upstream mitogen-activated protein kinase kinase (MEK) 1/2 was reduced by TIPE2. TIPE2 is negatively related with development of cervical squamous cancer. TIPE2 is an inhibitory factor of proliferation and invasion of cervical squamous cancer cells, probably through inhibiting Erk signaling pathway.

AGER promotes proliferation and migration in cervical cancer

The receptor for advanced glycation end products (AGER) is an oncogenic transmembranous receptor up-regulated in various human cancers. We have previously reported that AGER was overexpressed in squamous cervical cancer. However, mechanisms of AGER involved in the progression of cervical cancer are unknown. In the present study, we investigated the effects of AGER on biological behavior, including proliferation, apoptosis, and migration using multiple biological approaches. AGER protein primarily localized in the cytoplasm and cytomembrane of cervical squamous cancer cells. Blockage of AGER with multiple siRNAs suppressed proliferation, stimulated apoptosis, inhibited migration of cervical squamous cancer cells. Conversely, overexpression of AGER increased cell proliferation, migration, and inhibited cell apoptosis. These results indicate that AGER promotes proliferation, migration, and inhibits apoptosis of squamous cervical cancer and might function as a tumor promoter in cervical cancer. Our study provides novel evidence for a potential role of AGER in bridging human papillomavirus (HPV)-induced inflammation and cervical cancer.

Relationship Between High Density of Peritumoral Lymphatic Vessels and Biological Behavior of Cervical Cancer

ObjectiveTo investigate the relationship between lymphangiogenesis and lymphatic metastasis in cervical squamous carcinoma.MethodsEighty cases of invasive cervical squamous cancer were selected as objects of our study. Double immunohistochemical staining with antibodies against lymphatic vessel endothelial hyaluronan receptor 1 and Ki-67 was used to label the lymphatic vessels and mark the proliferative lymphatic vessels in cervical squamous cancer. The peritumoral lymphatic vessel density and intratumoral lymphatic vessel density was assessed. The lymphatic vessels proliferation index was evaluated by calculating Ki-67 proliferation index (PI) to reflect the lymphangiogenesis of cervical squamous cancer. Then the correlation between lymphangiogenesis and clinicopathologic features of cervical squamous cancer was analyzed.ResultsThe LVD of cervical cancer (15.23 ± 3.6) was clearly higher than that of the adjacent normal cervical subepithelial tissues (9.9 ± 2.5, P < 0.001). The peritumoral lymphatic vessel density of cervical cancer (18.75 ± 4.3) was significantly higher than the intratumoral lymphatic vessel density of cervical cancer (11.71 ± 4.9, P < 0.001). Lymphatic PI (LPI) of cervical cancer (0.258 ± 0.07) was higher than that of the adjacent normal cervical subepithelial tissues (0.068 ± 0.08, P < 0.001). The peritumoral lymphatic vessel PI of cervical cancer (0.324 ± 0.06) was notably higher than the intratumoral lymphatic vessel PI of cervical cancer (0.232 ± 0.06, P < 0.001). Peritumoral lymphatic vessel density and peritumoral lymphatic vessel were clearly associated with the lymph node metastasis (P = 0.001 and P = 0.002, respectively) and lymphovascular space invasion (P = 0.024 and P = 0.01, respectively).ConclusionsThe high density of peritumoral lymphatic vessels is a potential predictor of more aggressive phenotype of cervical squamous cancer.

Reduced expression of ΔΝp63α in cervical squamous cell carcinoma

Purpose: As a member of the p53 family, p63 is considered to be an important differentiation regulation transcriptional factor, but the roles of p63 in many epithelial tumourigenesis and metastasis processes are still not clear. This study was designed to investigate the expression of p63 and its isoform in normal tissues and squamous cell cancer tissues of uterine cervix, and its significance in cancer cell differentiation. Methods: The expression of p63 was assessed in cervical tissue and cell lines by immunohistochemistry, RT-PCR and Western Blotting. The relationships between p63 protein, various clinico-pathological features, and the differentiation marker involucrin were analyzed. Results: ΔΝp63α is the predominant isoform expressed in cervical epithelial tissues, and it is decreased in moderately or poorly differentiated cervical squamous carcinoma, as well as in the HeLa, SiHa and C33A cervical cancer cell lines. The expression level of ΔΝp63α was positively correlated with that of involucrin in cervical squamous cancer tissue, and the expression of ΔΝp63α is decreased with the degree of tumour invasion. Conclusion: The decrease of ΔΝp63α in cervical squamous cell cancer appears to be associated with the tumour progression, and ΔΝp63α may be a sensitive marker for cervical squamous cancer differentiation.