The search for highly sensitive and specific tumor biomarkers is essential for the evaluation of prognosis and new therapeutic targets. Immune cells in the tumor microenvironment (TME) have dual roles in promoting and suppressing tumor growth, which is crucial for the development and treatment of cancer. According to previous studies, syndecan binding protein (SDCBP) participated in biological processes like epithelial-mesenchymal transformation, angiogenesis, and exosome formation and secretion during cancer metastasis, but whether SDCBP affects immune cells infiltration in the TME remains unclear. Here, we conducted a comprehensive analysis of multiple databases to explore the expression and prognosis of SDCBP in pan-cancer and focused on the effect of SDCBP on the immune cells, particularly on macrophages. The study found that SDCBP was expressed at different levels in most tumor tissues and cells. Upregulation of SDCBP was associated with malignant progression, poor patient prognosis and treatment non-response in certain tumors. Gene set enrichment analysis suggested that SDCBP was mainly involved in regulating immunity and inflammation-related pathways, which may be closely associated with the high levels of immune cells infiltration. Further experiments confirmed that SDCBP is highly expressed in macrophages, and knockdown of SDCBP in THP-1-derived macrophages reduces their chemotaxis but does not affect their polarization and phagocytic function. Our study indicated that SDCBP involves in tumor progression and macrophages infiltration, providing novel perspectives for cancer, particularly in combination with immunotherapy.

BACKGROUND:Gastric cancer invades local tissue extensively and metastasizes through the circulation to remote organs. Patients with metastasized gastric cancer have poor clinical outcomes. The vasculature in the cancer niche is developed poorly, thus allowing cancer cells to be released into the circulation. However, it is poorly understood how cancer cells adhere to and transmigrate through the fully developed endothelium in remote organs and what key adhesive ligands are involved in the process. Here, we report results from a study designed to investigate the role of hyperadhesive VWF (von Willebrand factor) in promoting the pulmonary metastasis of gastric cancer. METHODS:We used mouse models to investigate the roles of hyperadhesive VWF in the pulmonary metastasis of gastric cancer. The findings from these mouse models were validated through in vitro experiments that specifically examined how VWF promoted gastric cancer-derived extracellular vesicles to activate endothelial cells and analyzed established databases of patients with gastric cancer. RESULTS:VWF in cancer-bearing mice became hyperadhesive and mediated the adhesion of gastric cancer-derived extracellular vesicles to the endothelium, where gastric cancer-derived extracellular vesicles caused endothelial permeability and promoted the transmigration of cancer cells to the interstitial tissue of the lungs. Reducing VWF adhesive activity by the metalloprotease ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type motifs, type 13) prevented the pulmonary metastasis of gastric cancer cells in mice. We further validated the findings in mice through targeted in vitro experiments and by associating VWF with the outcomes of patients with gastric cancer through established databases of patients with gastric cancer using bioinformatics tools. CONCLUSIONS:We show how VWF becomes hyperadhesive to promote the pulmonary metastasis of gastric cancer through its interaction with gastric cancer-derived extracellular vesicles and that the hyperadhesive activity of VWF is reduced by ADAMTS-13 to prevent the metastasis.

Gastric cancer is one of the most common malignant tumors in the world. The occurrence of chemotherapy resistance seriously affects the survival and prognosis of middle and advanced patients. Enhancing DNA repair ability is one of the important mechanisms of chemotherapy resistance. ADAM9, a member of the disintegrin and metalloproteinase family, is involved in many biological processes, such as tumor cells proliferation, apoptosis, invasion and migration, vascular invasion, and drug resistance. In this study, we found that the high expression of ADAM9 in gastric cancer tissues was associated with a variety of clinicopathological factors and poor prognosis in patients. Gastric cancer cells with high ADAM9 expression reduced sensitivity to Cisplatin, decreased DNA damage, increased expression of ATM and CHK2, the key proteins in DNA damage repair pathway, and improved cancer cells survival rate. Further studies showed that the expression of ADAM9 was selectively interfered with gastric cancer cells, the expression levels of ATM and CHK2 were decreased, while the expression of damage protein γ-H2AX was significantly increased, the degree of DNA damage was increased, and the sensitivity of gastric cancer cells to Cisplatin was significantly enhanced. It is suggested that ADAM9 is involved in Cisplatin resistance in gastric cancer cells, and its mechanism is related to the activation of ATM-CHK2 pathway in DNA damage repair. These data demonstrate that ADAM9 plays a pro-cancer role and mediates Cisplatin resistance in gastric cancer, which may be a new target to overcome chemotherapy resistance.

AIMS:Pulmonary fibrosis (PF) is always exacerbated by the comorbidity of lung adenocarcinoma (LUAD), and patients frequently died from the complications of PF instead of lung cancer. Although many studies have unveiled the mechanisms underlying PF exacerbation due to lung cancer resection and radiotherapy, the influence of lung cancer itself on PF remains enigmatic. MATERIALS AND METHODS:We cocultivated mouse pulmonary cells with mouse LUAD cells to explore the influence of LUAD on the pathogenesis and progression of PF. Additionally, a comorbidity model of PF with LUAD was established in mice via intratracheal injection of bleomycin (BLM) followed by in situ transplantation of LUAD cells. Furthermore, immunofluorescence, immunohistochemistry, and molecular analyses were employed to elucidate the mechanisms underlying the exacerbation of PF by the comorbidity of LUAD. KEY FINDINGS:We found that PF was significantly exacerbated by LUAD. In the microenvironment of LUAD, the epithelial-mesenchymal transition (EMT) was predominantly activated in lung epithelial cells, while the transformation of lung fibroblasts into myofibroblasts was markedly induced. The TGF-β and GSK-3β pathways were differentially activated in lung epithelial cells and fibroblasts. Furthermore, clinical samples confirmed the involvement of these pathways in the process of PF exacerbation induced by LUAD in patients' lung lesions of PF with LUAD. SIGNIFICANCE:This study initially reveals that LUAD exacerbates PF by modulating epithelial cells and fibroblasts through TGF-β and GSK-3β pathways differentially. Practically, targeting the pathways of TGF-β and GSK-3β may promise a potential strategy for the prophylaxis of PF exacerbation in patients with LUAD.

Extracellular vesicles (EVs) play a pivotal role in intercellular communication and are closely linked to cancer progression and metastasis. Our previous studies have shown that gastric cancer cell-derived EVs can promote tumor metastasis by increasing the permeability of the endothelial barrier. However, it remains unclear which effector molecule in the EV structure is the key factor of EV-mediated tumor metastasis and the underlying molecular mechanism. In this study, we found that CD147 is a key molecule highly expressed in gastric cancer-derived EVs and confirmed the role of CD147-high EVs from gastric cancer cells in promoting endothelial dysfunction and tumor metastasis. Our results showed that CD147-high EVs activated the VEGF/AKT/eNOS/NO and AKT/mTOR/p70S6K signaling pathways, leading to endothelial cytoskeletal reorganization and internalization of VE-cadherin, which significantly compromised endothelial barrier integrity, increased vascular leakage, enhanced transendothelial migration of tumor cell, and promoted the formation of metastatic tumors. Furthermore, detection of CD147 levels in gastric cancer tissues and plasma EVs indicated that high CD147 expression was associated with advanced tumor stage, poor prognosis, and reduced survival. Our findings suggest that CD147-high EVs are critical mediators of tumor-endothelial interactions and potential diagnostic and prognostic biomarkers for gastric cancer. Their potential as therapeutic targets for gastric cancer is underscored.

Gastric cancer remains a significant global health burden with limited treatment options and high mortality. Syndecan-binding protein (SDCBP), a scaffolding protein involved in tumor differentiation, has attracted attention as a potential therapeutic target in cancers. However, its precise role in gastric cancer progression is not fully understood. In this study, through bioinformatics analysis and gastric cancer samples detection, we discovered that SDCBP was highly expressed in gastric cancer tissues, which was correlated with clinicopathological features such as tumor invasion depth and distant metastasis, and exhibited heterogeneity across histological or molecular subtypes. Elevated SDCBP expression promoted the proliferation, invasion and migration of gastric cancer cells, and modulated epithelial-mesenchymal transition (EMT) via the ERK signaling pathway. Xenograft experiments in mice confirmed that inhibiting SDCBP or ERK signaling could delay cancer progression. We also found that gastric cancer cells with SDCBP knockdown were able to inhibit the M2 polarization of cocultured macrophages, reduce chemotaxis and enhance phagocytosis of macrophages. Therefore, SDCBP plays a crucial role in driving gastric cancer progression. Targeting SDCBP in gastric cancer can partially reverse the malignant phenotype, and SDCBP is expected to be a promising therapeutic target for gastric cancer.

ABSTRACT Cells of gastric cancer invade local tissue extensively and also metastasize through the circulation to remote organs. Patients with metastasized gastric cancer have poor outcomes. Cancer cells are known to release extracellular vesicles (EVs) that contribute to cancer progression, but how cancer cell-derived EVs promote cancer growth and metastasis remains poorly understood. We have recently reported that levels of circulating gastric cancer cell-derived EVs (gcEVs) and the adhesive ligand von Willebrand factor (VWF) are associated with cancer metastasis and poor prognosis of patients, but the underlying mechanism of this gcEV-VWF interaction was not known. Here we report results from a study designed to investigate the synergistic action of VWF and gcEVs in vitro and in mouse models. We showed that VWF in cancer-bearing mice was hyperadhesive and became microvesicle-bound. EV-bound VWF mediated the adhesion of gcEVs to the endothelium to disrupt endothelial integrity and facilitate the transendothelial migration of cancer cells and pulmonary metastasis. Reducing VWF adhesive activity by the metalloprotease ADAMTS-13 or promoting gcEV clearance by the scavenging factor lactadherin prevented pulmonary metastasis in mice. These results highlight the synergistic action of gcEVs and VWF in promoting gastric cancer metastasis and identifying new targets for its prevention. Key point: Author contributions Hyperadhesive VWF becomes microvesicle-bound to induce endothelial leakage and promote the pulmonary metastasis of gastric cancer in mice. Reducing VWF activity by ADAMTS-13 and accelerating microvesicle clearance by lactadherin reduces pulmonary metastasis of gastric cancer.

Von Willebrand factor (VWF) is an adhesive ligand critical for maintaining hemostasis. However, it has also been increasingly recognized for its role in cancer development because it has been shown to mediate the adhesion of cancer cells to endothelial cells, promote the epithelial–mesenchymal transition, and enhance angiogenesis. We have previously shown that gastric cancer cells synthesize VWF, which mediates the interaction between the cancer and endothelial cells to promote cancer growth. Here, we report results from a clinical observational study that demonstrate the association of VWF in plasma and on the surface of extracellular vesicles (EVs) with the pathological characteristics of gastric cancer. We found that patients with gastric cancer had elevated and intrinsically hyperadhesive VWF in their peripheral blood samples. VWF was detected on the surface of EVs from cancer cells, platelets, and endothelial cells. Higher levels of these VWF-bound EVs were associated with cancer aggression and poor clinical outcomes for patients. These findings suggest that VWF+ EVs from different cell types serve collectively as a new class of biomarkers for the outcome assessment of gastric cancer patients.

The endothelium is the critical barrier that controls transendothelial communications. Blood vessels in cancer tissue are poorly developed and highly permeable. However, it is poorly understood how circulating cancer cells released through these "leaky" vessels break the intact vasculature of remote organs to metastasize. We investigated the roles of cancer cell-derived extracellular vesicles (CEVs) in regulating cancer metastasis by analyzing samples from gastric cancer patients, performing in vitro experiments, and studying mouse models. We made several novel observations. First, the rate of metastasis was closely associated with plasma levels of CEVs in patients with gastric cancer. Second, cultured endothelial cells endocytosed CEVs, resulting in cytoskeletal rearrangement, low expression of the junction proteins cadherin and CD31, and forming large intercellular gaps to allow the transendothelial migration of cancer cells. The dynamin inhibitor Dynasore prevented these CEV-induced changes of endothelial cells by blocking CEVs endocytosis. Third, CEVs disrupted the endothelial barrier of cancer-bearing mice to promote cancer metastasis. Finally, lactadherin promoted the clearance of circulating CEVs to reduce metastasis. These results demonstrate the essential role of CEVs in promoting the metastasis of gastric cancer.

Tissue factor (TF) has been extensively studied for tumor metastasis, but its role in mediating cancer cell adhesion to vasculature remains unknown. This study aimed to measure the ability of TF to mediate the adhesion of breast cancer cells to human umbilical vein endothelial cells (HUVECs). MDA-MB-231 cells expressed the highest TF level and adhered more to HUVECs under static and flow conditions, a neutralizing TF antibody abolished the enhanced adhesion of MDA-MB-231 cells to HUVECs. Recombinant human soluble TF (rTF) bonded β1integrin on HUVECs surfaces, β1 or α3integrin antibody combined with TF antibody abolished more cell-cell adhesion. These data suggested that TF mediated adhesion of breast cancer cells to endothelial cells may rely on β1integrin on HUVECs surfaces.

Astragalus polysaccharide (APS) has been used as an adjuvant in the treatment of malignant tumors, however, most APS trials have been performed with chemotherapy of malignant tumors, the effect and mechanism of APS is unclear in radiotherapy for tumors. In the present study, the hepatocellular carcinoma H22 tumor-bearing mouse model was established. The H22 tumor-bearing mice received radiotherapy combined with APS treatment. Results showed APS could obviously up-regulate the expression of MHC class I chain-related molecule A (MICA) and B (MICB) on tumor cell surface, which is one of the major ligands of activating receptor NKG2D on natural killer cells (NK cells). The binding of MICA/B and NKG2D led to NK cell activation by improving the level of phosphorylated extracellular signal regulated kinase on NK cells. Activated NK cells released more IFN-gamma, Granzyme B and Perforin, promoting the clearance of tumor cells. These results suggested that APS increased the sensitivity of tumors to radiotherapy by activating the extracellular signal regulated kinase pathway of NK cells. APS may be as an efficient adjuvant in radiotherapy of malignant tumors.

已知血管性血友病因子(vWF)参与介导血小板对血管和微血管的粘附作用,并且vWF在慢性肾病患者血浆中的水平明显升高.为了揭示vWF和血管性血友病因子裂解酶(vWF-CP)在紫癜性肾炎患者血浆中的表达,以及vWF和vWF-CP在发病机制中的作用.本研究采用酶联免疫吸附试验(ELISA)和残余胶原蛋白结合试验分别检测紫癜性肾炎患者(HSPN组,n=62)、微小病变性肾小球病患者(MCN组,n=16)和健康体检者(对照组,n=10)血浆vWF水平和vWF-CP活性.应用免疫组织化学法检测肾组织中vWF和vWF-CP的表达.另外,应用ELISA检测了紫癜性肾炎患者血浆肿瘤坏死因子-α(TNF-α)水平,并分析了各指标间的相关性.研究结果显示,HSPN组和MCN组的vWF水平均显著高于对照组,而vWF-CP活性均显著低于对照组.随着ISKDC分级的升高,紫癜性肾炎患者的vWF水平逐渐升高.而vWF-CP活性则随着ISKDC分级的升高而显著降低.大量蛋白尿组(≥2.0 g/24 h)的vWF水平((183.4±27.37)％)显著高于非大量蛋白尿组(＜2.0 g/24 h,(132.64±19.79)％),而大量蛋白尿组的vWF-CP活性((44.47±6.63)％)显著低于非大量蛋白尿组((74.86±11.17)％).HSPN组和MCN组的TNF-α水平均显著高于对照组.在紫癜性肾炎患者和微小病变性肾小球病患者中,vWF的阳性表达率显著高于健康对照组(p＜0.05),而vWF-CP显著低于健康对照组(p＜0.05).紫癜性肾炎患者的vWF水平与TNF-α水平显著正相关(r=0.452,p=0.010),而vWF-CP活性与TNF-α水平显著负相关(r=-0.496,p=0.006).本研究初步结论表明vWF和vWF-CP参与紫癜性肾炎的发病机制,并且与病情严重程度密切相关,且vWF和vWF-CP的合成和分泌可能受到TNF-α等促炎症因子的调节.

Cancer prognosis is poor for patients with blood-borne metastasis. Platelets are known to assist cancer cells in transmigrating through the endothelium, but ligands for the platelet-mediated cancer metastasis remain poorly defined. von Willebrand factor (vWF) is a major platelet ligand that has been widely used as a biomarker in cancer and associated inflammation. However, its functional role in cancer growth and metastasis is largely unknown. Here we report that gastric cancer cells from patients and cells from two well-established gastric cancer lines express vWF and secrete it into the circulation, upon which it rapidly becomes cell-bound to mediate cancer-cell aggregation and interaction with platelets and endothelial cells. The vWF-mediated homotypic and heterotypic cell–cell interactions promote the pulmonary graft of vWF-overexpressing gastric cancer BGC823 cells in a mouse model. The metastasis-promoting activity of vWF was blocked by antibodies against vWF and its platelet receptor GP Ibα. It was also reduced by an inhibitory siRNA that suppresses vWF expression. These findings demonstrate a causal role of cancer-cell-derived vWF in mediating gastric cancer metastasis and identify vWF as a new therapeutic target.

Coat proteins (COPs), including the major types clathrin, COPI and COPII, play a considerable role in intracellular transport by initiating the formation of transport vesicles. Coatomer protein complex subunit β2 (COPB2) is one of the seven subunits that make up a COPI complex. In the present study, we found that COPB2 was highly expressed in human colon cancer specimens. However, to date, there have been no reports describing the functions of COPB2 in human colon cancer cells. In this study, we analyzed the functions of COPB2 in the proliferation and cell cycle arrest of human RKO and HCT116 colon cancer cells by using lentivirus-mediated RNAi infection. Our results demonstrated that the silencing of COPB2 in vitro could inhibit the proliferation and colony formation abilities of RKO and HCT116 cells. Furthermore, measurement of cell cycle distribution indicated that the downregulation of COPB2 could induce G0/G1 or S phase cell cycle arrest by regulating cell cycle-related proteins. In conclusion, our results suggest that COPB2 plays a key role in the proliferation and cell cycle progression of human RKO and HCT116 colon cancer cells, thus indicating that COPB2 might be a potential therapeutic target for the treatment of human colon cancer.

Epirubicin (EPI) is widely used for triple negative breast cancer (TNBC), but a substantial number of patients develop EPI resistance that is associated with poor outcome. The underlying mechanism for EPI resistance remains poorly understood. We have developed and characterized an EPI-resistant (EPI-R) cell line from parental MDA-MB-231 cells. These EPI-R cells reached stable growth in the medium containing 8 μg/ml of EPI. They overexpressed P-glycoprotein (P-gp) and contained numerous autophagic vacuoles. The suppression of P-gp overexpression and/or autophagy restored the sensitivity of these EPI-R cells to EPI. We further show that autophagy conferred resistance to EPI on MDA cells by blocking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated pro-apoptotic signals. Together, these results reveal a synergistic role of P-gp, autophagy, and NF-κB pathways in the development of EPI resistance in TNBC cells. They also suggest that blocking the P-gp overexpression and autophagy may be an effective means of reducing EPI resistance.

Objective To observe the autophagy induced by heavy ion and X-ray radiations in SW480 cells and its effect in radiation responses.Methods The cellular ultrastructure was observed with a transmission electron microscope (TEM).The autophagy vesicles were labeled by monodansylcadaverin (MDC) fluorescence.The levels of LC3 which were induced by radiation and rapamycin were measured by Western blot assay.Cell proliferation was detected by MTT assay.The invasion of SW480 colon cells was measured with a Transwell.Cell wound healing assay was used to observe the migration of SW480 colon cells.Results Heavy ion and X-ray radiation could induce autophagy in SW480 cells in a dose dependent manner i.e., the autophagy level increased along with irradiation dose (F =458.526, P ＜ 0.05) , but this induction of autophagy was inhibited by chloroquine.Rapamycin could also induce autophagy in SW480 cells and it had a synergistic effect with irradiation (F =189.393, P ＜ 0.05).The abilities of invasion, migration and proliferation of SW480 cells were reduced by irradiation and the combination treatment of irradiation and rapamycin (F =194.692, 629.917, 302.903, P ＜ 0.05) , but they were enhanced by chloroquine (F =194.692, 629.917, 302.903, P ＜ 0.05).Conclusions Ionization radiation causes cell death by inducing autophagy.

Gastric cancer is one of the most common malignancies and has a high rate of metastasis. We hypothesize that NME2 (Nucleoside Diphosphate Kinase 2), which has previously been considered as an anti-metastatic gene, plays a role in the invasiveness of gastric cancer cells. Using a tissue chip technology and immunohistochemistry, we demonstrated that NME2 expression was associated with levels of differentiation of gastric cancer cells and their metastasis into the lymph nodes. When the NME2 gene product was over-expressed by ;in vitro stable transfection, cells from BGC823 and MKN45 gastric cancer cell lines had reduced rates of proliferation, migration, and invasion through the collagen matrix, suggesting an inhibitory activity of NME2 in the propagation and invasion of gastric cancer. NME2 could, therefore, severe as a risk marker for gastric cancer invasiveness and a potential new target for gene therapy to enhance or induce NME2 expression.

Purpose To observe the effects of rapamycin-induced autophagy on the invasion,migration of SW480 colon cancer cells and to investigate the possible mechanism. Methods The autophagy vesicles were detected by monodansylcadaverin( MDC) fluorescence. The ultrastructure was observed under transmission electron microscope( TEM). The level of LC3 induced by rapamycin was detected by Western blotting. The invasion of SW480 colon cells was measured by Boyden chamber. Cell wound healing assay was used to observe the migration of SW480 colon cells. The level of ROS was analyzed using flow cytometry. Results The SW480 colon cells were purified with autophagic vesicle under rapamycin environment and autophagy level also increased in a time-dependent manner.The number of SW480 moving into the second floor was increased under the rapamycin environment( P < 0. 01),while the migration was also improved( P < 0. 05). The production of ROS increased as well. Conclusions Rapamycin can induce autophagy on SW480cell line. For SW480 colon cancer cells,the invasion and migration could be enhanced under the autophagy environment induced by rapamycin. The level of ROS also changes under this environment.

Objective To investigate the expression of chemokine receptor 4(CXCR4 ) and interleukin -6(IL-6) proteins in colorectal carcinoma and determine their clinical significance through finding their association with microvessel density(MVD) and their correlations with each other. Methods Immunohistochemistry staining was used to detect the expression of CXCR4,IL-6 proteins and CD34 in 94 cases of colorectal cancer tissues.Results The respective expression levels of CXCR4 and IL-6 in colorectal cancer tissues were 72.34%and 28.72%.Expression of CXCR4 in colorectal carcinoma was correlated with invasive depth and lynph node metastasis(P0.05). Expression of IL-6 in colorectal carcinoma was not correlated to invasive depth,lynph node metastasis or tumor locus of the colorectal carcinoma.The expression of IL-6 in colorectal carcinoma was correlated with MVD.The expression of CXCR4 had no correlation with the expression of IL-6 in colorectal carcinoma.The expression of CXCR4 was positively correlated with tumor invasive depth,lymph node metastasis and MVD in patients suffering from colorectal cancer. Conclusion The increase of the expression of CXCR4 and IL-6 in colorectal cancer tissue may relate with tumor angiogenesis and they may play a key role in colorectal cancer formation and metastasis.