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The molecular mechanism of tumor metastasis, especially how metastatic tumor cells colonize in a distant site, remains poorly understood. Here we reported that ARHGAP15, a Rho GTPase activating protein, enhanced gastric cancer (GC) metastatic colonization, which was quite different from its reported role as a tumor suppressor gene in other cancers. It was upregulated in metastatic lymph nodes and significantly associated with a poor prognosis. Ectopic expression of ARHGAP15 promoted metastatic colonization of gastric cancer cells in murine lungs and lymph nodes in vivo or protected cells from oxidative-related death in vitro. However, genetic downregulation of ARHGAP15 had the opposite effect. Mechanistically, ARHGAP15 inactivated RAC1 and then decreased intracellular accumulation of reactive oxygen species (ROS), thus enhancing the antioxidant capacity of colonizing tumor cells under oxidative stress. This phenotype could be phenocopied by inhibition of RAC1 or rescued by the introduction of constitutively active RAC1 into cells. Taken together, these findings suggested a novel role of ARHGAP15 in promoting gastric cancer metastasis by quenching ROS through inhibiting RAC1 and its potential value for prognosis estimation and targeted therapy. Author summary: Although metastasis is an extremely insufficient process, it constitutes the major cause of gastric cancer related death. Up to present, little is known about the metastatic colonization, especially how the quite limited tumor cells survive in distant sites to develop metastatic lesions. Here, we reported a Rho GTPase activating protein ARHGAP15, which was identified as a leading upregulated gene in metastatic lymph nodes but previously reported as a tumor suppressor in other malignancies, promoted metastatic colonization of gastric cancer in vivo and protected cell from oxidative-related death in vitro. Further studies indicated that ARHGAP15 suppressed RAC1 and then decreased intracellular reactive oxygen species produced by NOX2, a downstream gene of RAC1, thus protecting colonizing tumor cells from oxidative stress. Our research contributed to a more comprehensive and detailed understanding of the dynamics of metastatic colonization and more importantly, demonstrated the pro-metastatic role of ARHGAP15 for the first time, providing novel insights into the role of this Rho GTPase activating protein. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) are emerging as key molecules in human cancer genesis and progression, including prostate cancer. Large amount of lncRNAs have been found that differentially expressed between prostate cancer tissues and normal prostate tissues. Whether these lncRNAs could serve as a novel biomarker for prostate cancer diagnosis or prognosis, and their biological functions in prostate cancer need further investigation. In the present study, we identified that lncRNA lnc-MX1-1 is over-expressed in prostate cancer tissues compared with their adjacent normal prostate tissues by gene expression array profiling. The expression of lnc-MX1-1 in 60 prostate cancer cases was determined by real-time quantitative PCR and the correlations between lnc-MX1-1 expression and patients' clinical features were further analyzed. Next, we impaired lnc-MX1-1 expression using RNAi in LNCaP and 22Rv1 prostate cancer cells to explore the effects of lnc-MX1-1 on proliferation and invasiveness of the cells. Our results showed that there was a significant association between over-expression of lnc-MX1-1 and patients' clinical features such as PSA, Gleason score, metastasis, and recurrence free survival. Moreover, knockdown of lnc-MX1-1 reduced both proliferation and invasiveness of LNCaP and 22Rv1 cells. In conclusion, the results suggest that lnc-MX1-1 may serve as a potential biomarker and therapeutic target for prostate cancer. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether circular RNA hsa_circ_0002874 could serve as a novel biomarker for the diagnosis of gastric cancer (GC). The expression level of hsa_circ_0002874 mean (interquartile range [IQR]) in the plasma of patients with GC, patients with benign gastric lesions, and healthy individuals was 3.482 (IQR, 1.524–9.048), 1.261 (IQR, 0.817–2.000), and 1.00 (IQR, 0.726–1.382), respectively, whereas there was no significant difference between the latter 2 groups. The plasma expression level of hsa_circ_0002874 was significantly correlated with tumor stage (U  = 234.0; P < .001) and lymph node metastasis (U  = 240.0; P < .001). The receiver operating characteristic (ROC) curve showed that the sensitivity of the combined determination of hsa_circ_0002874 and the serum markers CEA and CA19-9 was 95.8% in patients with GC compared with that of the healthy group and 93.0% compared with that of patients with benign gastric tumor lesions. The specificity of hsa_circ_0002874 in differentiating GC from benign lesions was 98.3%. The results showed that plasma hsa_circ_0002874 may prove to be a useful biomarker for auxiliary diagnosis, the grading of malignant neoplasms, and the prognostic prediction of GC. [ABSTRACT FROM AUTHOR]

Background: Chromogranin A (CgA), synaptophysin (Syn) and the Ki-67 index play significant roles in diagnosis or the evaluation of the proliferative activity of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, little is known about whether these biological markers change during tumor metastasis and whether such changes have effect on prognosis. Methods: We analyzed 35 specimens of both primary and metastatic tumor from 779 patients who had been diagnosed as GEP-NENs at Wuhan Union Hospital from August 2011 to October 2019. The heterogeneity of CgA, Syn and Ki-67 index was evaluated by immunohistochemical analysis. Results: Among these 779 patients, the three most common sites of NENs in the digestive tract were the pancreas, rectum and stomach. Metastases were found in 311 (39.9%) patients. Among the 35 patients with both primary and metastatic pathological specimens, differences in the Ki-67 level were detected in 54.3% of the patients, while 37.1% showed a difference in CgA and only 11.4% showed a difference in Syn. Importantly, due to the difference in the Ki-67 index between primary and metastatic lesions, the WHO grade was changed in 8.6% of the patients. In addition, a Kaplan–Meier survival analysis showed that patients with Ki-67 index variation had a shorter overall survival (p = 0.0346), while neither Syn variation nor CgA variation was related to patient survival (p = 0.7194, p = 0.4829). Conclusions: Our data indicate that primary and metastatic sites of GEP-NENs may exhibit pathological heterogeneity. Ki-67 index variation is closely related to the poor prognosis of patients with tumor metastasis, but neither Syn variation nor CgA variation is related to patient prognosis. Therefore, clinicopathologic evaluation of the primary tumor and metastatic sites could be helpful for predicting the prognosis. [ABSTRACT FROM AUTHOR]

Tumor metastasis is a significant contributor to the mortality of cancer patients. Specifically, current conventional treatments are unable to achieve complete remission of brain metastasis. This is due to the unique pathological environment of brain metastasis, which differs significantly from peripheral metastasis. Brain metastasis is characterized by high tumor mutation rates and a complex microenvironment with immunosuppression. Additionally, the presence of blood-brain barrier (BBB)/blood tumor barrier (BTB) restricts drug leakage into the brain. Therefore, it is crucial to take account of the specific characteristics of brain metastasis when developing new therapeutic strategies. Nanomaterials offer promising opportunities for targeted therapies in treating brain metastasis. They can be tailored and customized based on specific pathological features and incorporate various treatment approaches, which makes them advantageous in advancing therapeutic strategies for brain metastasis. This review provides an overview of current clinical treatment options for patients with brain metastasis. It also explores the roles and changes that different cells within the complex microenvironment play during tumor spread. Furthermore, it highlights the use of nanomaterials in current brain treatment approaches. [Display omitted] • The unique pathological environment of brain metastases limits clinical outcomes. • Different cell types play different roles and change during the progression of BM. • NMs can be customized to specific pathological features and thus offer significant advantages in BM treatment. [ABSTRACT FROM AUTHOR]

Precisely reporting the inflammatory microenvironment, which can provide important basis for disease diagnosis and progression determination, is always challenging. In this work, we develop a targeting peptide-conjugated chemiluminescent reporter (OFF), which can be recognized by in-situ circulated neutrophils once injected, and then transported to the inflamed tissues characterized with overexpressed superoxide anion (O 2 −), assisted by the chemotaxis natural of neutrophils. Subsequently, the chemiluminescent probe can particularly respond to O 2 − to release the caged photons (ON) for visualizing inflammatory diseases such as subcutaneous tumor, colorectal cancer peritoneal metastasis (CCPM), ear swelling and kidney failure. The chemiluminescent probe provides a reliable tool to early detect inflammation and precisely excise micrometastatic lesions under optical guidance. This study provides a potential approach for improving the performance of luminophore in advanced bioimaging applications. [Display omitted] • An "off-to-on" chemiluminescent probe based on the structure of Schaap's dioxetanes is developed in this work • The probe transportation can inherit neutrophils' inherent inflammation-chemotaxis characteristic. • The probe can selectively respond to superoxide anion rich in inflammatory tissues. • The probe can specially and precisely image the foci of inflammatory disease. [ABSTRACT FROM AUTHOR]

Platelets play a vital physiological role in hemostasis, inflammation and tissue regeneration, which are associated with wound healing as well as cancer development and metastasis. These years, a variety of platelet-mediated drug delivery approaches have been developed due to their unique properties, such as quick replenishment and site-specific activation/adhesion. In this Current Opinion , focuses are put on strategies leveraging the physiological functions of platelets for the design of drug delivery systems, including platelet engineering, platelet hitchhiking, membrane coating, synthetic platelet fabrication and platelet-triggered drug release for different applications. [ABSTRACT FROM AUTHOR]

A versatile tumor‐targeting stimuli‐responsive theranostic platform for peritoneal metastases of colorectal cancer is proposed in this work for tumor tracking and photothermal‐enhanced chemotherapy. A quenched photosensitizer ("off" state) is developed and escorted into a tumor‐targeting oxaliplatin‐embedded micelle. Once reaching the tumor cell, the micelle is clasped to release free oxaliplatin, as well as the "off" photosensitizer, which is further activated ("turned‐on") in the tumor reducing microenvironment to provide optical imaging and photothermal effect. The combined results from hyperthermia‐enhanced chemotherapy, deep penetration, perfused O2, and the leveraged GSH‐ROS imbalance in tumor cells are achieved for improved antitumor efficacy and reduced systematic toxicity. [ABSTRACT FROM AUTHOR]

A previous study by our group demonstrated that overexpression of KAI1 was associated with lymphatic metastasis in pancreatic cancer. The present study further investigated the signaling pathways involved in KAI1-induced downregulation of vascular endothelial growth factor C (VEGF-C) and lymphatic metastasis in pancreatic cancer. Immunohistochemistry was performed to examine KAI1 and VEGF-C expression in 28 surgically resected pancreatic cancer tissues. MIA PaCa-2 and PCAN1 pancreatic cancer cell lines were transfected with KAI1 overexpression vector. VEGF-C expression as well as phosphorylation of Src and signal transducer and activator of transcription (STAT)3 were assessed by western blot analysis. Furthermore, the signal transduction inhibitors PP2 and AG490 were used to block the Src and STAT3 signaling pathways, respectively. KAI1 was negatively correlated with VEGF-C expression in pancreatic tumor samples. In MIA PaCa-2 cells, VEGF-C expression was more significantly inhibited by restoration of KAI1 than that in PCAN1 cells. In addition, Src and STAT3 phosphorylation was decreased by KAI1 in MIA PaCa-2 cells. Of note, pre-treatment with PP2 efficiently reversed the KAI1-induced enhancement of Src and STAT3 phosphorylation as well as VEGF-C expression. Pre-treatment with AG490 efficiently reversed the KAI1-induced enhancement of STAT3 phosphorylation and VEGF-C expression, but had no effect on the upregulation of Src phosphorylation. The present study identified the involvement of Src/STAT3 signaling pathways in KAI1-induced downregulation of VEGF-C expression and suggested the implication of these pathways in lymphatic metastasis of pancreatic cancer. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effects of PTEN and KAI1 gene overexpression on the proliferation, metastasis and radiosensitivity of ASPC-1 pancreatic cancer cells under hypoxic conditions. Recombinant vectors that overexpress PTEN and KAI1 genes were transfected into hypoxic ASPC-1 cells. Protein expression levels were detected by western blot analysis. An MTT cell growth curve assay and a colony-forming assay were used to analyze cell proliferation, and a Transwell assay was performed to evaluate the metastatic ability of the cells. Annexin V flow cytometry was used to determinate the apoptotic rate of X-ray-treated ASPC-1 cells. Western blot analysis revealed that PTEN- and KAI1-transfected ASPC-1 cells significantly upregulated PTEN and KAI1 expression. The proliferation of hypoxic ASPC-1 cells was significantly suppressed by PTEN and KAI1. Furthermore, PTEN and KAI1 overexpression inhibited the metastatic ability of hypoxic ASPC-1 cells. Following X-ray treatment, the percentage of apoptotic cells increased significantly in the ASPC-1 cells transfected with PTEN and KAI1, which demonstrated that hypoxic ASPC-1 cells were more radiosensitive due to PTEN and KAI1 overexpression. In conclusion, double overexpression of PTEN and KAI1 inhibited the proliferation and metastatic activity, and enhanced apoptosis induced by X-ray in ASPC-1 cells under hypoxic conditions, which indicates that PTEN and KAI1 double-expression may have valuable application in pancreatic cancer gene therapy. [ABSTRACT FROM AUTHOR]

In article number 1806620, Chen Jiang and co‐workers, inspired by the ability of activated platelets to track tumor metastasis, develop a novel activated plateletstargeting micelle for efficient anticancer drug delivery to primary and metastatic tumors. After specifically binding to activated platelets in circulation, the micelles capture circulating tumor cells (CTCs) through the "platelet bridge" and eliminate CTCs to prevent metastasis. [ABSTRACT FROM AUTHOR]

The frequent relapse and metastasis characteristics of triple negative breast cancer (TNBC) make it a fraught issue with very poor prognosis in clinic. An effective treatment for TNBC should prevent and even eliminate metastasis as well as suppress primary lesion expansion. Recent progress reveals that platelets can be recruited and activated by tumor cells through intercellular adhesion molecules (ICAM), and help aggressive circulating tumor cells (CTCs) form metastasis. Therefore, activated platelets are considered with possession of tumor‐homing, CTC‐capturing, and metastasis‐targeting abilities. In this work, a P‐selectin (expressed on activated platelet surface) targeting peptide (PSN) is modified on a redox‐responsive paclitaxel‐loaded micelle (PSN‐PEG‐SS‐PTX4 micelle) to utilize activated platelets as a "bridge" for interaction with cancer cells. The PSN‐modified micelle can easily adhere to the surface of activated platelets and subsequently capture CTCs in blood circulation. Compared to Taxol and PEG‐SS‐PTX4 micelle, PSN‐PEG‐SS‐PTX4 micelle also exhibits enhanced primary TNBC/metastasis targeting and penetrating effect through binding with tumor infiltrating platelets and thus significantly improves treatment outcome. More importantly, PSN‐PEG‐SS‐PTX4 micelle potently suppressed lung metastasis of TNBC and reduced incidence of distant liver metastasis. The activated platelet‐targeting redox‐responsive micelle system provides a promising prospect for the omnidirectional treatment of metastatic cancer. A novel P‐selectin targeting micelle with controlled drug release is designed to utilize activated platelets as an endogenous device for efficient drug delivery to metastatic tumors. The micelle captures and eliminates circulating tumor cells via binding with activated platelets to prevent metastasis as well as penetrates and accumulates at primary tumors or metastasis via tumor‐infiltrating activated platelets. [ABSTRACT FROM AUTHOR]