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The prognostic impact and treatment responses among cervical cancer patients with different histological types remains inconclusive. To determine the prognostic effects of different histologic types, we identified 39,088 patients with a diagnosis of cervical cancer between 2004 and 2016 from the Surveillance, Epidemiology, and End Results program.Variables related to the prognosis of cervical cancer were evaluated using log-rank method and univariate/multivariate Cox models before and after propensity score matching.Of the 36,310 patients, Squamous cell carcinoma (SCC) was the most common histological type (n = 27,043, 74.5%), followed by adenocarcinoma (AC, n = 7755, 21.4%) and adenosquamous carcinoma (ASC, n = 1512, 4.1%). Compared to SCC patients, patients with AC (HR = 1.14, 95%CI = 1.09-1.20, P 0.01) and ASC (HR = 1.28, 95%CI = 1.18-1.40, P 0.01) showed significantly poorer prognosis. Subgroup analyses indicated that the differences in prognosis between AC and SCC were only observed in stage II and III patients (P 0.01). In patients with concurrent chemoradiotherapy, survival rates of patients with AC were significantly worse compared with similar patients with SCC (HR = 1.14, 95%CI = 1.03-1.27; P 0.01).The prognostic impact of histologic types among patients with cervical cancer depends on tumor stages and therapeutic approaches. Tailored treatment and follow-up planning need to be developed across patients with different histological types and stages.

Metastasis is one of the most threatening aspects of cervical cancer. We developed a method to intraoperatively map the primary tumor, metastasis and metastatic sentinel lymph nodes (SLNs), providing real-time intraoperative guidance in cervical cancer. Methods: TMTP1, a tumor metastasis targeting peptide, was employed to modify the indocyanine green (ICG)-loaded poly (ethylene glycol)- poly (lactic-co-glycolic acid) (PEG-PLGA) micelles. The cervical cancer subcutaneous tumor model and lung metastasis model were established to determine the active targeting of ICG-loaded TMTP1-PEG-PLGA micelles (ITM) for the primary tumor and occult metastasis of cervical cancer. Human cervical cancer HeLa cells engineered by firefly luciferase were injected into the right hocks of BALB/c nude mice to develop the SLN metastasis model. The ITM and control ICG-loaded PEG-PLGA micelles (IM) were injected into the right hind footpads in the SLN metastasis model, and the migration and retention of micelles were recorded under near-infrared fluorescence. K14-HPV16 transgenic mice were also used to detect the image capability of ITM to target cancerous lesions. Results: ITM could actively target imaging of the primary tumor and cervical cancer metastasis. ITM quickly diffused from the injection site to SLNs along lymphatic capillaries and remained in the SLNs for 12 h. Moreover, ITM specifically accumulated in the tumor metastatic SLNs (T-SLNs), which could be successfully distinguished from normal SLNs (N-SLNs). Conclusion: ITM could achieve active targeting of the primary tumor, metastasis and T-SLNs, providing precise and real-time intraoperative guidance for cervical cancer.

As we reported in our previous studies, TMTP1, a tumor-homing peptide, selectively targets highly metastatic tumors and their metastatic foci. Aminopeptidase P2 (XPNPEP2) is a receptor for TMTP1 tumor-homing peptide. However, the biological and clinical significance of Aminopeptidase P2 in human cancers remains unknown. In this study, the high-density multiple organ tumor tissue array was employed for the analysis of XPNPEP2 expression profiles in human specimens. The results showed that XPNPEP2 was moderately expressed in the normal prostate tissues, but significantly decreased in the prostate cancer. Hence we used TCGA, IHC, and ELISA to further analyze the expression of XPNPEP2 in tissues and serum of prostate cancer patients. In general, XPNPEP2 expression was lower in prostate cancer tissue than in normal prostate tissue, but was higher in prostate cancer tissues with local invasion and LN metastasis than in tissues with localized Pca. Western blot clarified XPNPEP2 had a secreted form in the serum. Then the serums of 128 Pca patients, 70 healthy males and 40 prostate hyperplasia patients were obtained for detecting serum XPNPEP2 levels.The results indicated that the concentration of XPNPEP2 in serums of Pca patients with LN metastasis (142.7 ± 14.40 ng/mL) were significantly higher than levels in Pca patients without LN metastasis (61.63 ± 5.50 ng/mL) (p

// Rui Wei 1 , Mengqin Lv 1, * , Fei Li 1 , Teng Cheng 1 , Zhengzhong Zhang 1 , Guiying Jiang 1 , Ying Zhou 1 , Ruiqiu Gao 1 , Xiao Wei 1 , Jicheng Lou 1 , Xizi Wu 1 , Danfeng Luo 1 , Xiangyi Ma 1 , Jin Jiang 2 , Ding Ma 1 and Ling Xi 1 1 Cancer Biology Research Center, Key Laboratory of The Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China 2 Department of Molecular Biology, UT Southwestern Medical Center at Dallas, TX, Dallas, USA * Co-first author Correspondence to: Ling Xi, email: lxi@tjh.tjmu.edu.cn Keywords: ovarian cancer, hedgehog signaling, cancer associated fibroblasts, VEGF-C, lymphangiogenesis Received: October 07, 2016 Accepted: May 01, 2017 Published: June 27, 2017 ABSTRACT Cancer-associated fibroblasts (CAFs) play a pivotal role in the development and progression of many human cancers. Recent studies have shown that Hedgehog (Hh) signalling modulates the stromal microenvironment and prepares a suitable niche for tumour metastasis. However, the detailed molecular mechanisms underlying CAF-mediated lymphangiogenesis have not been fully elucidated. Therefore, our goal is to illustrate whether Hh ligands can activate Hh signalling in CAFs in a paracrine fashion and elucidate the effect of CAFs on lymphangiogenesis. We determined here that Sonic Hedgehog (SHH) secreted by ovarian cancer (OC) cells activated Hh signalling in CAFs and promoted the proliferation of CAFs. Moreover, we co-injected SHH-overexpressing OC cells and CAFs in a xenograft model and found that the CAFs accelerated tumourigenesis and lymphangiogenesis in OC. Mechanistically, we found that SHH secreted by the OC cells induced VEGF-C expression in CAFs. Inhibition of Hh signalling in CAFs decreased VEGF-C expression and diminished the positive role of CAFs in supporting tumourigenesis and lymphangiogenesis in a murine xenograft model. Our results demonstrate that CAFs constitute a supportive niche for cancer lymphangiogenesis via the Hh/VEGF-C signalling axis and provide evidence for the clinical application of Hh inhibitors in the treatment of OC.

// Qian Sun 1 , Haiyue Zhao 1 , Cong Zhang 1 , Ting Hu 1 , Jianli Wu 1 , Xingguang Lin 1 , Danfeng Luo 1 , Changyu Wang 1 , Li Meng 1 , Ling Xi 1 , Kezhen Li 1 , Junbo Hu 1 , Ding Ma 1 and Tao Zhu 1 1 Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China Correspondence to: Tao Zhu, email: zhutao@tjh.tjmu.edu.cn Keywords: ovarian cancer, WGCNA, gene co-expression network, grade, stage Received: October 13, 2016 Accepted: April 15, 2017 Published: May 11, 2017 ABSTRACT Serous ovarian cancer (SOC) is the most lethal gynecological cancer. Clinical studies have revealed an association between tumor stage and grade and clinical prognosis. Identification of meaningful clusters of co-expressed genes or representative biomarkers related to stage or grade may help to reveal mechanisms of tumorigenesis and cancer development, and aid in predicting SOC patient prognosis. We therefore performed a weighted gene co-expression network analysis (WGCNA) and calculated module-trait correlations based on three public microarray datasets (GSE26193, GSE9891, and TCGA), which included 788 samples and 10402 genes. We detected four modules related to one or more clinical features significantly shared across all modeling datasets, and identified one stage-associated module and one grade-associated module. Our analysis showed that MMP2, COL3A1, COL1A2, FBN1, COL5A1, COL5A2, and AEBP1 are top hub genes related to stage, while CDK1, BUB1, BUB1B, BIRC5, AURKB, CENPA, and CDC20 are top hub genes related to grade. Gene and pathway enrichment analyses of the regulatory networks involving hub genes suggest that extracellular matrix interactions and mitotic signaling pathways are crucial determinants of tumor stage and grade. The relationships between gene expression modules and tumor stage or grade were validated in five independent datasets. These results could potentially be developed into a more objective scoring system to improve prediction of SOC outcomes.

In our previous study, a tumor-homing peptide, TMTP1, selectively targets to the highly metastatic tumors and its metastatic foci. Aminopeptidase P2(XPNPEP2) is a receptor for TMTP1 tumor-homing peptide. However, the biological and clinical significance of Aminopeptidase P2 in human cancers remains unknown. In this study, the high-density multiple organ tumor tissue array was employed for the profile of XPNPEP2 expression in human specimens. The results showed that XPNPEP2 was moderately expressed in the prostate, but significantly decreased in the prostate cancer. Moreover, XPNPEP2 acts synergistically with kallikrein during bradykinin production. Hence we used TCGA, IHC and Elisa to analyze the expression of XPNPEP2 in tissues and serum of prostate cancer patients. XPNPEP2 expression was lower in prostate cancer tissue than in normal prostate tissue, but was higher in Prostate cancer tissue with local invasion and LN metastasis than in tissue with localized Pca. Western blot clarified XPNPEP2 had a secreted form in the serum. Then the serum of 128 Pca patients along with 70 healthy males and 40 prostate hyperplasia patients were obtained for detecting serum XPNPEP2 levels. Serum XPNPEP2 levels in Pca patients with LN metastasis (142.7±14.40 ng/mL) were significantly higher than levels in Pca patients without LN metastasis (61.63±5.50 ng/mL) (P

// Haiyue Zhao 1, * , Ensong Guo 1, * , Ting Hu 1 , Qian Sun 1 , Jianli Wu 1 , Xingguang Lin 1 , Danfeng Luo 1 , Chaoyang Sun 1 , Changyu Wang 1 , Bo Zhou 1 , Na Li 1 , Meng Xia 1 , Hao Lu 1 , Li Meng 1 , Xiaoyan Xu 1 , Junbo Hu 1 , Ding Ma 1 , Gang Chen 1 , Tao Zhu 1 1 Cancer Biology Research Center (Key Laboratory of the Ministry Of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China * These authors have contributed equally to this work Correspondence to: Tao Zhu, email: tjogzt@gmail.com Gang Chen, email: chengang@tjh.tjmu.edu.cn Keywords: serous ovarian cancer, recurrence, prognosis, KCNN4 , S100A14 Received: November 26, 2015 Accepted: May 8, 2016 Published: May 30, 2016 ABSTRACT Approximately 50-75% of patients with serous ovarian carcinoma (SOC) experience recurrence within 18 months after first-line treatment. Current clinical indicators are inadequate for predicting the risk of recurrence. In this study, we used 7 publicly available microarray datasets to identify gene signatures related to recurrence in optimally debulked SOC patients, and validated their expressions in an independent clinic cohort of 127 patients using immunohistochemistry (IHC). We identified a two-gene signature including KCNN4 and S100A14 which was related to recurrence in optimally debulked SOC patients. Their mRNA expression levels were positively correlated and regulated by DNA copy number alterations (CNA) ( KCNN4 : p= 1.918e-05) and DNA promotermethylation ( KCNN4 : p= 0.0179; S100A14 : p= 2.787e-13). Recurrence prediction models built in the TCGA dataset based on KCNN4 and S100A14 individually and in combination showed good prediction performance in the other 6 datasets (AUC:0.5442-0.9524). The independent cohort supported the expression difference between SOC recurrences. Also, a KCNN4 and S100A14-centered protein interaction subnetwork was built from the STRING database, and the shortest regulation path between them, called the KCNN4-UBA52-KLF4-S100A14 axis, was identified. This discovery might facilitate individualized treatment of SOC.

XPNPEP2 is a proline hydrolytic enzyme that hydrolyzes several biologically active peptides and causes a loss of substrate activity. However, its function in cancer is still unknown. Our study showed that XPNPEP2 expression was significantly upregulated in cervical cancer tissues compared with normal cervical tissues and cervical intraepithelial neoplasm tissues. Statistical analysis showed that XPNPEP2 expression was associated with the International Federation of Gynecology and Obstetrics stage and lymph node metastasis. Overexpression of XPNPEP2 in SiHa and HeLa cells promoted cell invasion and migration without affecting cell proliferation and apoptosis. Mechanistically, we found that XPNPEP2 facilitated cervical cancer cell invasion and migration by inducing epithelial–mesenchymal transition. Furthermore, we demonstrated that XPNPEP2 had significant effects on the metastasis of xenografted tumors in vivo. Collectively, our findings identify the novel function of XPNPEP2 in the metastasis of cervical cancer and suggest that XPNPEP2 could be a novel potential therapeutic target for the treatment of cervical cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells and enhance therapy in vivo. However, concerns regarding its considerable liver toxicity limit its use in humans as a cancer therapy. Tumor molecular targeted peptide 1 (TMTP1) has previously been reported by our laboratory to target primary tumors and metastatic foci. Here, we report a novel recombinant fusion protein, sTRAIL-TMTP1, which not only induced apoptosis in cancer cells in vitro but also inhibited tumor growth and metastases in vivo. Moreover, sTRAIL-TMTP1 impacted tumor angiogenesis. The biodistribution results demonstrated that sTRAIL-TMTP1 accumulation peaked 6 h after injection and persisted for 24 h in the tumor, while faint sTRAIL-TMTP1 accumulation was detected in normal organs in tumor-bearing mice. Thus, combining sTRAIL with TMTP1 resulted in high anti-tumor activity and low toxicity. In conclusion, the novel fusion protein sTRAIL-TMTP1 was successfully developed in our laboratory and was observed to induce apoptosis both in primary and metastatic cancer, which may lead to the development of novel, targeted anticancer agents.Construction, purification, and characterization of the novel recombinant fusion protein, sTRAIL-TMTP1. sTRAIL-TMTP1 not only induce apoptosis in cancer cells but inhibit tumor growth and metastasis. sTRAIL-TMTP1 showed an impact on caspase activity and tumor angiogenesis. sTRAIL-TMTP1's accumulate in tumor with little accumulation in normal organs.

Introduction TMTP1 (NVVRQ) is a novel tumor-homing peptide, which specifically targets tumor metastases, even at the early stage of occult metastasis foci. Fusing TMTP1 to therapeutic peptides or proteins can increase its anti-cancer efficacy both in vivo and in vitro. Here, we labeled TMTP1 with 99m Tc to evaluate its targeting properties in an ovarian cancer xenograft tumor mouse model and a gastric cancer xenograft mouse model. Methods The invasion ability of SKOV3 and highly metastatic SKOV3.ip cell lines were performed by the Transwell Invasion Assays, and then Rhodamine-TMTP1 was used to detect its affinity to these two cells. Using the co-ligand ethylenediamine- N , N ′-diacetic acid (EDDA) and the bifunctional chelator 6-hydrazinonicotinic acid (HYNIC), the TMTP1 peptide was labeled with 99m Tc. A cell-binding assay was performed by incubating cancer cells with 99m Tc-HYNIC-TMTP1 with or without an excess dose of cold HYNIC-TMTP1. To evaluate the probe in vivo, nude mice bearing SKOV3, SKOV3.ip and MNK-45 tumor cells were established and subjected to SPECT imaging after injection with 99m Tc-HYNIC-TMTP1. Ex vivo γ-counting of dissected tissues from the mice was used to evaluate its biodistribution. Results 99m Tc-HYNIC-TMTP1 was successfully synthesized. The radiotracer also exhibited high hydrophilicity and excellent stability in vitro and in vivo. It has strong affinity to highly metastatic cancer cell lines but not to poorly metastatic cell lines. After mice were injected with 99m Tc-HYNIC-TMTP1, non-invasive SPECT imaging detected SKOV3.ip and MNK-45 xenograft tumors but not SKOV3 xenograft tumors. This result can be inhibited by excess HYNIC-TMTP1. The uptake of 99m Tc-HYNIC-TMTP1 in SKOV3.ip xenograft tumors was 0.182±0.017% ID/g at 2h p.i. with high renal uptake (74.32±15.05% ID/g at 2h p.i.). Conclusion 99m Tc-HYNIC-TMTP1 biodistribution and SPECT imaging demonstrated its ability to target highly metastatic tumors. Therefore, metastasis can be non-invasively investigated by SPECT imaging using 99m Tc-HYNIC-TMTP1. Meanwhile, this radiotracer has some shortages in the low % ID/g of tumors and high accumulation in the kidney.

Purpose: Tumor metastasis continues to be the major obstacle to cancer therapy and the leading cause of cancer-related death. Methods used to detect metastasis, especially occult metastases, have received a great deal attention. In this study, a novel selective peptide was assessed for its specific binding to metastasis. Methods: The FliTrx bacterial peptide display system, an alternative to phage peptide display, was used to identify a 5-amino acid peptide termed TMTP1 (NVVRQ), which binds to the highly metastatic prostate cancer cell line PC-3M-1E8. The synthetic TMTP1 was tested in vitro for its binding specificity and affinity to highly metastatic cancer cells. The tumor targeting assays were done in vivo by i.v. injection of FITC-conjugated TMTP1 into tumor-bearing mice. Results: TMTP1 specifically bound to a series of highly metastatic tumor cells, including prostate cancer PC-3M-1E8, breast cancer MDA-MB-435S, lung cancer PG-BE1, and gastric cancer MKN-45sci, in vitro and in vivo but not to the poorly metastatic or nonmetastatic cell line, including prostate cancer PC-3M-2B4, breast cancer MCF-7, lung cancer PG-LH7, or murine fibroblast cell NIH/3T3. FITC-TMTP1 strongly and specifically targeted the metastasis foci in tumor-bearing mice 24 h after i.v. peptide injection. Moreover, the occult metastases were specifically detected by FITC-TMTP1. Conclusion: Our results suggest that TMTP1 is a potential strategy for the development of new diagnostic tracers or alternative anticancer agents for tumor metastasis.