Abstract Regulatory roles of tetraspanins in cellular metabolism are emerging from multiple lines of studies on physiological and pathological events such as cancer, stem cell, inflammation, and steatosis and involved in lipid, amino acid, and carbohydrate metabolisms. Metabolic enzyme, metabolite transporter, and even metabolite are found to associate with and/or be components of tetraspanin-enriched membrane domains (TEMDs) and may reciprocally modulate the functionality of TEMDs. Precise roles and mechanisms of the interaction between tetraspanins and cellular metabolism remain to be delineated, and impacts of tetraspanins and TEMDs on systemic metabolism remain to be determined. This article synthesizes current mechanistic insights into tetraspanin-mediated metabolic regulation, with an emphasis on transporter control, subcellular compartmentalization, and signaling integration. We discuss how TEMDs may represent underexplored pharmacological nodes and outline future directions where systems pharmacology, omics-driven target discovery, and membrane-focused drug design could leverage tetraspanins to modulate metabolic disease and cancer.

Tetraspanin CD82/KAI1 inhibits cell movement and metastasis of malignant tumors, and reduced and lost expressions of CD82 predict worse outcomes of patients with malignant tumors. Here we found that CD82 inhibits both solitary and collective movement of tumor cells. The CD82 YVAA mutation, which affects CD82 trafficking, selectively abrogates CD82-mediated inhibition of collective migration. Cilengitide, at the concentration that specifically inhibits integrin αVβ3, also selectively blocks collective movement, underscoring a promotive role of integrin αVβ3 in this mode of cell motility. In contrast, integrin αVβ5 appears non-essential for collective migration, and both αVβ3 and αVβ5 are dispensable for solitary movement on fibronectin, highlighting distinct functions of different integrins in different modes of tumor cell movement. CD82 interacts with αVβ3 and αVβ5 integrins and downregulates their protein levels, while CD82 YVAA mutation relinquishes this downregulation without disrupting CD82 interactions with these integrins. Mechanistically, CD82, but not the YVAA mutant, considerably reduces digitation junction—the structure where integrin αVβ3 localizes—and likely directs integrin αVβ3 for lysosomal degradation, thereby lowering its level and suppressing collective migration. Thus, our study reveals that i) integrin αVβ3 promotes collective movement of tumor cells, ii) CD82 counteracts this by diminishing integrin αVβ3 and its presence in microextrusions, and iii) digitation junction likely participates in collective cell movement. Our study further demonstrates that endolysosomal trafficking of CD82 and integrin αVβ3 is needed for their collective movement-regulatory activities and that coupling of metastasis suppressor CD82/KAI1 with different partners regulates different modes of cell movement.

Tetraspanins affect metastasis, stemness and angiogenesis, but their roles in inflammation remain to be further clarified. Here we show that endothelial ablation of tetraspanin Cd82 markedly reduces vascular inflammation by mitigating endothelial leakage. Mechanistically, by limiting the anchorages of Cdc42 activator FARP1 and RhoA inhibitor Rnd3 to the plasma membrane (PM), CD82 confines Cdc42 but maintains RhoA activity in endothelial cells, to facilitate endothelium activation. These signaling regulatory effects depend on the ability of CD82 to coalesce and retain accessible cholesterol (AC) at the PM, whereas simvastatin overturns CD82 effects by lowering AC. CD82 supports non-vesicular transfer of AC to the PM through oxysterol-binding protein-related proteins (ORPs). Thus, CD82 and AC promote vascular leakage, whereas statin and ORP inhibitor restrain vascular leakage by decreasing AC. These findings reveal an unconventional anti-inflammation role and mechanism for statin and conceptualize tetraspanin-mediated, AC-mediated and cholesterol transfer-mediated balancing of antagonistic GTPase signaling pathways as regulatory mechanisms for vascular leakage. By regulating the level of accessible cholesterol on endothelial cells via OSBP/ORP-mediated transport, tetraspanin tunes the balance of Cdc42 and RhoA activities to affect vascular inflammation. Reducing accessible cholesterol by statin treatment or blocking its non-vesicular transport by OSBP/ORP inhibition can limit vascular inflammation.

BACKGROUND:Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown.METHODS:In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events.RESULTS:Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase.CONCLUSIONS:Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

Inflammation can impair intestinal barrier, while increased epithelial permeability can lead to inflammation. In this study, we found that the expression of Tspan8, a tetraspanin expressed specifically in epithelial cells, is downregulated in mouse model of ulcerative disease (UC) but correlated with those of cell–cell junction components, such as claudins and E-cadherin, suggesting that Tspan8 supports intestinal epithelial barrier. Tspan8 removal increases intestinal epithelial permeability and upregulates IFN-γ-Stat1 signaling. We also demonstrated that Tspan8 coalesces with lipid rafts and facilitates IFNγ-R1 localization at or near lipid rafts. As IFN-γ induces its receptor undergoing clathrin- or lipid raft-dependent endocytosis and IFN-γR endocytosis plays an important role in Jak-Stat1 signaling, our analysis on IFN-γR endocytosis revealed that Tspan8 silencing impairs lipid raft-mediated but promotes clathrin-mediated endocytosis of IFN-γR1, leading to increased Stat1 signaling. These changes in IFN-γR1 endocytosis upon Tspan8 silencing correlates with fewer lipid raft component GM1 at the cell surface and more clathrin heavy chain in the cells. Our findings indicate that Tspan8 determines the IFN-γR1 endocytosis route, to restrain Stat1 signaling, stabilize intestine epithelium, and subsequently prevent intestine from inflammation. Our finding also implies that Tspan8 is needed for proper endocytosis through lipid rafts.

Experimental studies on immunoglobulin superfamily (IgSF) member EWI2 reveal that it suppresses a variety of solid malignant tumors including brain, lung, skin, and prostate cancers in animal models and inhibits tumor cell movement and growth in vitro. While EWI2 appears to support myeloid leukemia in mouse models and maintain leukemia stem cells. Bioinformatics analyses suggest that EWI2 gene expression is downregulated in glioblastoma but upregulated in melanoma, pancreatic cancer, and liver cancer. The mechanism of action for EWI2 is linked to its inhibition of growth factor receptors and cell adhesion proteins through its associated tetraspanin-enriched membrane domains (TEMDs), by altering the cell surface clustering and endolysosome trafficking/turnover of these transmembrane proteins. Recent studies also show that EWI2 modulates the nuclear translocation of ERK and TFEB to change the activities of these gene expression regulators. For EWI2 relatives including FPRP, IgSF3, and CD101, although their roles in malignant diseases are not fully clear and remain to be determined experimentally, FPRP and IgSF3 likely promote the progression of solid malignant tumors while CD101 seems to modulate immune cells of tumor microenvironment. Distinctive from other tumor regulators, the impacts of EWI subfamily members on solid malignant tumors are likely to be context dependent. In other words, the effect of a given EWI subfamily member on a tumor probably depends on the molecular network and composition of TEMDs in that tumor. Collectively, EWI2 and its relatives are emerged as important regulators of malignant diseases with promising potentials to become anti-cancer therapeutics and cancer therapy targets.

EWI2 is a transmembrane immunoglobulin superfamily (IgSF) protein that physically associates with tetraspanins and integrins. It inhibits cancer cells by influencing the interactions among membrane molecules including the tetraspanins and integrins. The present study revealed that, upon EWI2 silencing or ablation, the elevated movement and proliferation of cancer cells in vitro and increased cancer metastatic potential and malignancy in vivo are associated with (i) increases in clustering, endocytosis, and then activation of EGFR and (ii) enhancement of Erk MAP kinase signaling. These changes in signaling make cancer cells (i) undergo partial epithelial-to-mesenchymal (EMT) for more tumor progression and (ii) proliferate faster for better tumor formation. Inhibition of EGFR or Erk kinase can abrogate the cancer cell phenotypes resulting from EWI2 removal. Thus, to inhibit cancer cells, EWI2 prevents EGFR from clustering and endocytosis to restrain its activation and signaling.

As a partner of tetraspanins, EWI2 suppresses glioblastoma, melanoma, and prostate cancer; but its role in lung cancer has not been investigated. Bioinformatics analysis reveals that EWI2 gene expression is up regulated in lung adenocarcinoma and higher expression of EWI2 mRNA may predict poorer overall survival. However, experimental analysis shows that EWI2 protein is actually downregulated constantly in the tissues of lung adenocarcinoma and lung squamous cell carcinoma. Forced expression of EWI2 in human lung adenocarcinoma cells reduces total cellular and cell surface levels of various integrins and growth factor receptors, which initiates the outside-in motogenic and mitogenic signaling. These reductions result in the decreases in 1) cell-matrix adhesion, cell movement, and cell transformation in vitro and 2) tumor growth, burden, and metastasis in vivo, and result from the increases in lysosomal trafficking and proteolytic degradation of theses membrane receptors. EWI2 elevates lysosome formation by promoting nuclear retention of TFEB, the master transcription factor driving lysosomogenesis. In conclusion, EWI2 as a lung cancer suppressor attenuates lung cancer cells in a comprehensive fashion by inhibiting both tumor growth and tumor metastasis; EWI2 as an endolysosome regulator promotes lysosome activity to enhance lysosomal degradation of growth factor receptors and integrins and then reduce their levels and functions; and EWI2 can become a promising therapeutic candidate given its accessibility at the cell surface, dual inhibition on growth factor receptors and integrins, and broad-spectrum anti-cancer activity. More importantly, our observations also provide a novel therapeutic strategy to bypass the resistance to EGFR inhibitors.

Background: Tetraspanins and integrins are integral membrane proteins. Tetraspanins interact with integrins to modulate the dynamics of adhesion, migration, proliferation, and signaling in the form of membrane domains called tetraspanin-enriched microdomains (TEMs). TEMs also contain other cell adhesion proteins like immunoglobulin superfamily (IgSF) proteins and claudins. Cardiovascular functions of these TEM proteins have emerged and remain to be further revealed. Objectives: The aims of this study are to explore the roles of these TEM proteins in the cardiovascular system using bioinformatics tools and databases and to highlight the TEM proteins that may functionally associate with cardiovascular physiology and pathology. Methods: For human samples, three databases-GTEx, NCBI-dbGaP, and NCBI-GEO-were used for the analyses. The dbGaP database was used for GWAS analysis to determine the association between target genes and human phenotypes. GEO is an NCBI public repository that archives genomics data. GTEx was used for the analyses of tissue-specific mRNA expression levels and eQTL. For murine samples, GeneNetwork was used to find gene-phenotype correlations and gene-gene correlations of expression levels in mice. The analysis of cardiovascular data was the focus of this study. Results: Some integrins and tetraspanins, such as ITGA8 and Cd151, are highly expressed in the human cardiovascular system. TEM components are associated with multiple cardiovascular pathophysiological events in humans. GWAS and GEO analyses showed that human Cd82 and ITGA9 are associated with blood pressure. Data from mice also suggest that various cardiovascular phenotypes are correlated with integrins and tetraspanins. For instance, Cd82 and ITGA9, again, have correlations with blood pressure in mice. Conclusion: ITGA9 is related to blood pressure in both species. KEGG analysis also linked ITGA9 to metabolism and MAPK signaling pathway. This work provides an example of using integrated bioinformatics approaches across different species to identify the connections of structurally and/or functionally related molecules to certain categories of diseases.

Dual blockade of phosphoinositide 3-kinase (PI3K) and poly(ADP-ribose) polymerase (PARP) has been revealed to be an effective treatment strategy for breast, ovarian and prostate cancer. However, the efficacy of this combination for the treatment of gastric cancer, and potential predictive therapeutic biomarkers remain unclear. Recent evidence suggests that the deficiency of AT-rich interactive domain containing protein 1A (ARID1A), which is a crucial chromatin remodeling gene, sensitizes tumor cells to PI3K and PARP inhibitors. Herein, we evaluated the therapeutic role of the combined treatment of PI3K inhibitor BKM120 and PARP inhibitor olaparib on gastric cancer cells, and explored ARID1A as a predictive biomarker. The results demonstrated that combined treatment with PI3K and PARP inhibitors effectively inhibited proliferation detected by MTS and clonogenic assay, invasion and migration by Transwell assay, of gastric cancer cells with ARID1A deficiency. Mechanistically, dual blockade of PI3K and PARP in ARID1A-depleted gastric cancer cells significantly increased apoptosis detected by flow cytometry, and induced DNA damage by immunofluorescent staining. Taken together, these data suggest that the combined treatment with PI3K inhibitor BKM120 and PARP inhibitor olaparib may be a promising therapeutic regimen for the treatment of gastric cancer, and ARID1A deficiency could serve as a potential predictive therapeutic biomarker.

Pancreatic cancer is among the most aggressive human cancers, and is resistant to regular chemotherapy and radiotherapy. The AT-rich interactive domain containing protein 1A (ARID1A) gene, a crucial chromatin remodeling gene, mutates frequently in a broad spectrum of cancers, including pancreatic cancer. Recent evidence suggests that ARID1A acts as tumor suppressor and plays an important role in DNA damage repair (DDR). However, the effect of ARID1A on the radiosensitivity of pancreatic cancer remains unclear. Herein, we investigated the involvement of ARID1A depletion in the radioresistance of pancreatic cancer cells, and explored the underlying mechanisms. The results reveal that knockdown of ARID1A enhances the radioresistance of pancreatic cancer cells through suppressing apoptosis, impairing G2-M checkpoint arrest, strengthening DDR, and accompanying activation of PI3K/AKT signaling pathway. Moreover, upon inhibition of PI3K/AKT pathway by PI3K-inhibitor LY294002 or AKT-inhibitor mk2206, the radiosensitivity of ARID1A-deficient pancreatic cancer cells is improved in vitro via increased apoptosis and weakened DDR. Taken together, these data suggest that loss of ARID1A expression enhances radioresistance of pancreatic cancer through activation of PI3K/AKT pathway, which maybe a promising target for radiosensitization of ARID1A-deficient pancreatic cancer.

The original version of the article unfortunately contained mistakes in Table 1, Fig. 1, Fig. 2a and 4a . In control groups (including ND and HCD groups), we misused the same data from our previously published paper “J Cardiovasc Pharmacol, 2008, 51(2):188–195”. We sincerely apologize for this carelessness. The corrected Table 1 and Fig. 1, Fig. 2, Fig. 4 are shown below. This correction does not influence the validity of the results and conclusions of the original article.Table 1Changes in plasma lipids, Ang II, AT1R mRNA of the aorta and blood pressure in high cholesterol-diet apolipoprotein E knock-out mice after treated with irbesartan.NDHCDHCD + IrbTotal cholesterol (mg/dl)584.24 ± 61.791562.41 ± 187.89⁎P<0.01 vs. the ND group.1604.89 ± 188.06⁎P<0.01 vs. the ND group., ⁎⁎P>0.05 vs. the HCD group.Triglyceride (mg/dl)92.64 ± 7.23177.49 ± 13.36⁎P<0.01 vs. the ND group.180.69 ± 9.78⁎P<0.01 vs. the ND group., ⁎⁎P>0.05 vs. the HCD group.Angiotensin II (pg/ml)182.4 ± 17.53285.64 ± 26.07⁎P<0.01 vs. the ND group.196.27 ± 18.77⁎⁎⁎P<0.05 vs. the HCD group.AT1R mRNA (arbitrary unit)1.00 ± 0.991.87 ± 0.13⁎P<0.01 vs. the ND group.1.04 ± 0.11⁎⁎⁎P<0.05 vs. the HCD group.SBP (mm Hg)95.7 ± 1.596.7 ± 1.794.3 ± 1.9⁎⁎P>0.05 vs. the HCD group.SBP, systolic blood pressure; Irb, irbesartan 10 mg kg−1d−1. Values are the mean ± SEM, n = 15 for each group. P < 0.01 vs. the ND group. P > 0.05 vs. the HCD group. P < 0.05 vs. the HCD group. Open table in a new tab Fig. 2Expression of Rac and p47phox in the atherosclerotic aorta of ApoE KO mice. A: The mRNA levels of Rac and p47phox were assayed by quantitative real-time reverse-transcription polymerase chain reaction. Each bar represents mean ± SEM (n = 6 per group). B: The protein levels of p47phox in membrane extract and Rac-GTP were measured by western blots. B (1): The representative results of western blots of p47phox and Rac-GTP are shown. B (2): Densitometric measurements of p47phox and Rac-GTP from western blots. Each bar represents mean ± SEM (n = 3). Irb, irbesartan 10 mg kg−1 d−1. *P < 0.01 vs. the ND group; #P < 0.01 vs. the HCD group.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 4Expression of TNF-α, IL-6, MCP-1 and VCAM-1 in the atherosclerotic aorta of ApoE KO mice. A: The mRNA levels for TNF-α, IL-6, MCP-1 and VCAM-1 were assayed by quantitative real-time reverse transcription polymerase chain reaction. Each bar represents mean ± SEM (n = 6 per group). B: The protein levels of TNF-α, IL-6, MCP-1 and VCAM-1 were measured by western blots. B (1): The representative results of western blots of TNF-α, IL-6, MCP-1 and VCAM-1 are shown. B (2): Densitometric measurements of TNF-α, IL-6, MCP-1 and VCAM-1 from western blots. Each bar represents mean ± SEM (n = 3). Irb, irbesartan 10 mg kg−1 d−1. *P < 0.01 vs. the ND group; #P < 0.01 vs. the HCD group; +P < 0.05 vs. the ND group.View Large Image Figure ViewerDownload Hi-res image Download (PPT) SBP, systolic blood pressure; Irb, irbesartan 10 mg kg−1d−1. Values are the mean ± SEM, n = 15 for each group. Molecular mechanisms of irbesartan suppressing atherosclerosis in high cholesterol-diet apolipoprotein E knock-out miceInternational Journal of CardiologyVol. 139Issue 2PreviewAtherosclerosis is a chronic inflammatory disease in which the renin–angiotensin–aldosterone system plays an important role. Evidence indicate that the angiotensin type 1 receptor blockers can suppress atherogenesis, but the exact mechanisms have not been fully elucidated. The study was undertaken to investigate the potential effects and molecular mechanisms of an angiotensin type 1 receptor blocker irbesartan on atherogenesis in high cholesterol-diet apolipoprotein E knock-out mice. Full-Text PDF

Background— Angiogenesis is crucial for many pathological processes and becomes a therapeutic strategy against diseases ranging from inflammation to cancer. The regulatory mechanism of angiogenesis remains unclear. Although tetraspanin CD82 is widely expressed in various endothelial cells (ECs), its vascular function is unknown. Methods and Results— Angiogenesis was examined in Cd82 -null mice with in vivo and ex vivo morphogenesis assays. Cellular functions, molecular interactions, and signaling were analyzed in Cd82 -null ECs. Angiogenic responses to various stimuli became markedly increased upon Cd82 ablation. Major changes in Cd82 -null ECs were enhanced migration and invasion, likely resulting from the upregulated expression of cell adhesion molecules such as CD44 and integrins at the cell surface and subsequently elevated outside-in signaling. Gangliosides, lipid raft clustering, and CD44-membrane microdomain interactions were increased in the plasma membrane of Cd82 -null ECs, leading to less clathrin-independent endocytosis and then more surface presence of CD44. Conclusions— Our study reveals that CD82 restrains pathological angiogenesis by inhibiting EC movement, that lipid raft clustering and cell adhesion molecule trafficking modulate angiogenic potential, that transmembrane protein modulates lipid rafts, and that the perturbation of CD82-ganglioside-CD44 signaling attenuates pathological angiogenesis.

The heavy metal inventory and the ecological risk of the tidal flat sediments in Haizhou Bay were investigated. Results show that the average concentrations of heavy metals in the surface sediments exceeded the environment background values of Jiangsu Province coastal soil, suggesting that the surface sediments were mainly polluted by heavy metals (Cd, Cr, Cu, Mn, Pb and Zn). In addition, the profiles of heavy metals fluxes can reflect the socio-economic development of Lianyungang City, and heavy metals inputs were attributed to anthropogenic activities. Cr, Cu, Pb and Zn were mainly present in the non-bioavailable residual form in surface sediments, whereas Cd and Mn were predominantly in the highly mobile acid soluble and reducible fractions. The ecological risk of the polluted sediments stemmed mainly from Cd and Pb. According to the Sediment quality guidelines (SQGs), however, the adverse biological effects caused by the heavy metals occasionally occurred in tidal flat.

Coastal zone could be considered as an important sink of regional source to sink and preserve historical records of environmental evolution. Four sediment cores, collected from tidal flat at Haizhou Bay near Lianyungang City, were examined for concentrations of heavy metals including Cd, Cr, Cu, Mn, Pb and Zn in core sediments to investigate the historical input of trace metals. In addition, sediment rates of cores LH3 and LH4 were determined based on radionuclide 210Pb. The results showed that grain size control effect was not the main factor that influenced the distribution of heavy metals. Heavy metals concentrations in the surface sediments were higher than these regional background values. Furthermore, Al element as a proxy of grain size was selected for normalization and calculation of metal enrichment factor (EF) and anthropogenic heavy metal fluxes. The results revealed that heavy metals in tidal flats were continuously enriched in the past decades, meanwhile, tidal flats have been significantly subjected to contaminations due to anthropogenic activities. Moreover, the depth profiles of heavy metals fluxes correspond to scenario of social-economy development of Lianyungang, which is an important urban area near Haizhou Bay. From 1950s to 2005, anthropogenic fluxes of metals increased with fluctuations, whereas, since 2005 anthropogenic fluxes declined, which may be correlated to the adjustment of industrial structure as well as the strengthened environmental regulation.

The sedimentation of metals can preserve the historical record of contaminant input from local and regional sources and provide information on the historical changes in regional water and sediment quality. We report the 210Pb activities and the heavy metal (Cd, Cr, Cu, Mn, Pb and Zn) depth profiles from sediment cores retrieved in 2010. The mean sedimentation rates of 0.85–1.5 cm/yr are determined by 210Pb dating. The sediments in the tidal flat have recorded heavy metal deposition and thus allow the establishment of a connection between the temporal evolution of the heavy metal pollution and the historical changes in the economic development of Lianyungang. The enrichment factors (EF) are calculated to estimate the level of contamination stored in these sediments. The results show that in the studied sites, Cr and Cu display low EF values and are mainly from lithogenic origin. For the other studied trace metals, a great variability in the sedimentary record is observed. Significant anthropogenic enrichment over the last 50 years is revealed at the tidal flat that receives fluvial inputs. Zinc is the element with the highest EF values, followed by the order of Pb > Cd > Mn > Cu and Cr. The temporal variations of the heavy metals peak during the late 1980s to the early 2000s and show a decreasing trend afterward. The pollution intensity of the tidal flat is determined by using EF and the geo-accumulation index (Igeo), which show that, based on the Igeo scale, the tidal flat of Haizhou Bay is unpolluted to moderately polluted.

Objective: To investigate the incidence and management of hypertension induced by sorafenib in patients with advanced renal cell carcinoma, and to evaluate the relationship between hypertension and the response to sorafenib. Methods: The incidence of blood pressure in 30 patients with advanced renal cell carcinoma treated with sorafenib was calculated and the severity of hypertension was classified as grade 1 to grade 5. The corresponding antihypertensive therapy was conducted and the change of blood pressure after treatment was observed. The predictive value of hypertension for the response to sorafenib was evaluated by using univariate analysis. Results: The median time from the initiation of sorafenib treatment to the occurrence of sorafenib-induced hypertension in 30 patients with advanced renal cell carcinoma was 15 d (range: 6-58 d). The incidence of sorafenib-induced hypertension was 30.0% (9/30). In these 9 patients, most (88.9%) of them were classified as grade 1 to grade 2 of hypertension. The hypertension was controlled well after corresponding antihypertensive treatment. No serious cardiac events or hypertensive crisis were observed. The dose of sorafenib was not reduced or the sorafenib treatment was not interrupted due to the uncontrolled hypertension. Univariate analysis revealed that sorafenib-induced hypertension was not a significant predictor for the response to sorafenib (χ2=0.635，P=0.637).Conclusion: The incidence of sorafenib-induced hypertension during the treatment of advanced renal cell carcinoma is high, but the severity of this hypertension is mostly mild or moderate, and the response to antihypertensive treatment is satisfying. The sorafenib-induced hypertension is not a predictor for the response to sorafenib. DOI:10.3781/j.issn.1000-7431.2012.05.013

Objective To investigate the clinical outcome,adverse events and turnover of sorafenib in advanced renal cell carcinoma patients,and to evaluate the long-term efficacy and safety of sorafenib.Methods Documented the clinical outcome, survival status,adverse events and turnover in 33 advanced renal cell carcinoma patients treated with sorafenib.Results 33 advanced renal cell carcinoma patients received sorafenib treatment.The median time of follow-up was 56 weeks(12～98 weeks).Among the 33 patients,1 patient had complete remission(CR,3.0%),5 patients got partial remission(PR, 15.2%),21 patients had stable disease(SD,63.6%) and 6 patients had progression of disease(PD,18.2%).The objective response rate(ORR) was 18.2%,the disease control rate(DCR) was 81.8%,the median progression-free survival (PFS) was 15.0 months(95%CI 6.5 -23.5) and the median overall survival(OS) was 24.0 months(95%CI 7.6～40.4).The sorafenib-related adverse events mainly included hand-foot skin reaction(HFSR),diarrhea,hypertension,fatigue, rash and alopecia.Most of the adverse events were classified as grade 1 to grade 2,except for HFSR.After proper corresponding management,most of the adverse events alleviated.Conclusion In advanced renal cell carcinoma patients,the long-term efficacy and safety of sorafenib are satisfying.