"Triple-Punch" Strategy Exosome-Mimetic Nanovesicles for Triple Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is the most malignant breast cancer, with high rates of relapse and metastasis. Because of the nonspecific targeting of chemotherapy and insurmountable aggressiveness, TNBC therapy lacks an effective strategy. Exosomes have been reported as an efficient drug delivery system (DDS). CD82 is a tumor metastasis inhibitory molecule that is enriched in exosomes. Aptamer AS1411 specifically targets TNBC cells due to its high expression of nucleolin. We generated a "triple-punch" cell membrane-derived exosome-mimetic nanovesicle system that integrated with CD82 overexpression, AS1411 conjugation, and doxorubicin (DOX) delivery. CD82 enrichment effectively inhibits the migration of TNBC cells. AS1411 conjugation specifically targets TNBC cells. DOX loading effectively inhibits proliferation and induces apoptosis of TNBC cells. Our results demonstrate a system of exosome-mimetic nanovesicles with "triple-punch" that may facilitate TNBC therapeutics.

Factors Influencing Mandibular Deviation: A Retrospective Clinical Study.

This study aimed to investigate the correlation between mandibular deviation (MD) and possible clinical factors in patients with anterior disc displacement (ADD). This retrospective clinical study enrolled 296 patients with ADD, diagnosed using magnetic resonance imaging, from 2015 to 2018. The clinical symptoms and medical histories of these patients were carefully examined and recorded. Mandibular deviation was the primary outcome variable confirmed by a combination of clinical examination and facial photographs or posteroanterior cephalograms. The primary predictor variable was ADD staging. Secondary predictor variables included condylar height and distance of disc displacement. Other predictor variables were age, sex, disease course, oral parafunctions, depression, and bone mineral density. We used logistic regression to examine the correlation between the MD and all predictor variables. The χ2 test and analysis of variance were used to exclude the correlation between the predictor variables. In this study, the prevalence of MD was 77% among 278 patients with ADD. Bilateral ADD staging significantly contributed to MD on both sides. The odds ratio increased with the deterioration of disc displacement. The present study demonstrated that the ADD staging influences the condylar height and MD, and that articular disk position should be considered while treating MD.

Four-Color SERS Monitoring of Size-dependent Nanoparticle Delivery in the Same Tumor.

The physicochemical properties of nanoparticles (NPs) significantly influence their deposition at the disease site, ultimately impacting the overall therapeutic efficacy; however, precisely assessing the effects of various factors on NP accumulation within a single cell/tumor tissue is challenging due to the lack of appropriate labeling techniques. Surface-enhanced Raman spectroscopy (SERS) tag is a powerful encoding method that has recently been intensively employed for immunodetection of biomarkers. Herein, we introduce a multiplexed SERS tracking approach for systematic investigation of size-dependent accumulation and distribution of NPs within the same tumor. Four-sized (34, 60, 108, and 147 nm) NPs encoded with different SERS "colors" were fabricated, mixed, and incubated with monolayer tumor cells, multicellular tumor spheroids, or injected into mouse models bearing xenograft solid tumors in a single dose. Multicolor SERS detection of the specimens revealed that NP accumulation in tumor cells, tumor spheroids, and solid tumors was in the order of 34 nm > 60 nm > 108 nm > 147 nm, 60 nm > 34 nm > 108 nm > 147 nm, and 34 nm > 147 nm > 108 nm > 60 nm, respectively. Inductively coupled plasma mass spectroscopy determination performed in parallel samples were in alignment with the four-color SERS probing results, demonstrating the effectiveness of this multiplexed evaluation assay. Furthermore, in combination with fluorescence labeling of specific biomolecules, this method can be applied for the colocalization of different NPs in various pathological structures and provide additional information for analysis of the possible mechanisms.

An integrated bioinformatics analysis of the S100 in head and neck squamous cell carcinoma.

Background: This study aims to evaluate the expression profile and clinical value of the S100 family in head and neck squamous cell carcinoma (HNSCC). Methods: The expression patterns, clinicopathological features, prognostic significance and underlying correlations of S100 family genes in HNSCC were determined by bioinformatics analysis with the application of several databases, including the The Cancer Genome Atlas (TCGA) and Oncomine for differential expression gene (DEG) analysis, and a series of analysis tools, including Database for Annotation, Visualization and Integrated Discovery (DAVID), cBioPortal, Kaplan-Meier Plotter, Tumor Immune Estimation Resource (TIMER) and R software packages. Results: The results from the study demonstrated that S100A4, S100A10, and S100A13 may act as prognostic markers through overall survival (OS), disease-free survival (DFS) and tumor infiltrating immune cell enrichment and a prognostic S100 family gene model comprising S100A1-A4, S100A8, S100A10, S100A12, and S100A13 was identified. The messenger RNA (mRNA) expression of S100A1, S100A9, S100A14, and S100A7A was significantly different in HNSCC patients, together with a high mutation rate of the S100 family was found. Evaluation of clinicopathological value demonstrated the heterogeneity of S100 family functions. S100A1, S100A7, S100A8, S100A9, S100A13, S100A14, and S100A16 were observed to significantly correlate with multiple biological processes (BPs) of HNSCC, including initiation, lymph node metastasis, and lymphovascular invasion. In addition, the S100 family were significantly associated with epithelial-mesenchymal transition (EMT)-related genes. Conclusions: This present study demonstrated that S100 family members are implicated in the initiation, progression, metastasis and survival of HNSCC.

Extracellular vesicles promotes liver metastasis of lung cancer by ALAHM increasing hepatocellular secretion of HGF.

Tumor-derived extracellular vesicles (EVs) are involved in tumor metastasis. Highly enriched lncRNA-ALAHM was identified from serum EVs of lung adenocarcinoma (LUAD) patients with liver metastasis by high-throughput sequencing. A mouse model of in situ lung cancer was used to determine the effect of ALAHM in LUAD cell EVs on liver metastasis. The effects of ALAHM on hepatocyte paracrine HGF as well as proliferation, invasion, and migration of LUAD cells were observed in vitro. As results, ALAHM expression in LUAD cell EVs was significantly increased. LUAD-cell-derived EVs overexpressing ALAHM significantly promoted lung cancer liver metastasis in model mice. ALAHM of LUAD cell EVs also promotes hepatocyte parasecretion of HGF by binding with AUF1 and increases the proliferation, invasion, and migration of LUAD cells. Thus, LUAD-cell-derived EVs containing ALAHM causes increasing HGF and promoting liver metastasis of LUAD cells.

Combined legumain- and integrin-targeted nanobubbles for molecular ultrasound imaging of breast cancer.

Molecular ultrasound imaging is a promising strategy for non-invasive and precise cancer diagnosis. Previously reported ultrasound contrast agents (UCAs) are mostly microbubbles or nanobubbles (NBs) larger than 200 nm, leading to less efficient tumor delivery. Here we synthesized NBs with a small size (~49 nm) and modified the NB surface with alanine-alanine-asparagine (NB-A) or arginine-glycine-aspartic acid peptide (NB-R) for concurrent active targeting towards legumain in tumor cells and integrin in tumor neovasculature. In vitro, the NB-A and NB-R presented echogenicity comparable with SonoVue MBs and showed specific binding with tumors cells and endothelial cells, respectively. In vivo, the combined NB-A/NB-R accumulated in tumor tissues selectively and provided ultrasound signals with prolonged duration and that were significantly stronger than non-targeted NBs, single-targeted NBs and SonoVue MBs. Overall, the dual targeted NBs served as efficient UCAs for specific imaging of breast cancer, and hold great potential for general cancer diagnosis/monitoring in the future.

Asparagine endopeptidase-targeted Ultrasound-responsive Nanobubbles Alleviate Tau Cleavage and Amyloid-ß Deposition in an Alzheimer's Disease Model.

Inhibition of asparagine endopeptidase (AEP) has been implied to be effective for treating tau- and amyloid-beta-mediated neurodegenerative diseases, although a method for targeted intracerebral delivery of AEP inhibitors has not yet been achieved. Here, we fabricated ultrasound-responsive nanobubbles (NBs) to load AEP inhibitor RR-11a, and modified the NB surface with either AEP recognizable peptide AAN or pro-transendothelial transversal motif RGD, i.e. NB(11a)-A and NB(11a)-R, for AEP-targeted treatment of Alzheimer's disease (AD). The developed NBs were uniform, small in size (50.1 ± 1.5 nm), with strong echogenicity and high drug loading efficiency (∼91.97%). When intravenously co-injected in the APP/PS1 mouse model, NB(11a)-R could adhere to endothelial cells and enhance transient opening of the blood-brain barrier (BBB) upon focused ultrasound oscillations, allowing the rest NBs/localized released RR-11a molecules to enter the brain, and then NB(11a)-A could selectively bind with the impaired neurons and deposit RR-11a molecules at the AD lesion. As a result, co-administration of NB(11a)-A and NB(11a)-R significantly promoted accumulation of RR-11a in the mouse brain, and substantially alleviated both tau cleavage and amyloid plaques deposition in the hippocampus. Most strikingly, the cognitive ability of the AD model mice was dramatically improved, achieving a level close to the normal mice. Overall, this unique AEP-targeted nanobubble design provides an efficient intracerebral drug delivery strategy and significantly enhances treatment efficacy of AD. STATEMENT OF SIGNIFICANCE: Asparagine endopeptidase (AEP) is an innovative therapeutic target simultaneously involved in Aß and tau-mediated Alzheimer's disease (AD) pathology, but targeted delivery of AEP inhibitors has not been achieved yet. Here we developed an efficient strategy to deliver AEP inhibitor RR-11a towards impaired neurons. We fabricated RR-11a-loaded ultrasound-responsive nanobubbles (NBs) and modified the NB surface with RGD peptide to promote BBB crossing upon focused ultrasound oscillations, or with AAN peptide to increase binding of NBs on the neurons. Our results indicated that, co-administration of the NB(11a)-A and NB(11a)-R significantly enhanced accumulation of RR-11a molecules at the AD lesion, alleviated both tau cleavage and amyloid plaques deposition in the hippocampus, and consequently restored cognitive function of the AD model mice.

High TSPAN8 expression in epithelial cancer cell-derived small extracellular vesicles promote confined diffusion and pronounced uptake.

Small extracellular vesicles (sEVs) play a key role in intercellular communication. Cargo molecules carried by sEVs may affect the phenotype and function of recipient cells. Epithelial cancer cell-derived sEVs, particularly those enriched in CD151 or tetraspanin8 (TSPAN8) and associated integrins, promote tumour progression. The mechanism of binding and modulation of sEVs to recipient cells remains elusive. Here, we used genetically engineered breast cancer cells to derive TSPAN8-enriched sEVs and evaluated the impact of TSPAN8 on target cell membrane's diffusion and transport properties. The single-particle tracking technique showed that TSPAN8 significantly promoted sEV binding via confined diffusion. Functional assays indicated that the transgenic TSPAN8-sEV cargo increased cancer cell motility and epithelial-mesenchymal transition (EMT). In vivo, transgenic TSPAN8-sEV promoted uptake of sEVs in the liver, lung, and spleen. We concluded that TSPAN8 encourages the sEV-target cell interaction via forced confined diffusion and significantly increases cell motility. Therefore, TSPAN8-sEV may serve as an important direct or indirect therapeutic target.

Cancer-derived exosomal miR-138-5p modulates polarization of tumor-associated macrophages through inhibition of KDM6B.

Rationale: Differential activation of macrophages correlates closely with tumor progression, and the epigenetic factor lysine demethylase 6B (KDM6B, previously named JMJD3) mediates the regulation of macrophage polarization through an unknown mechanism. Methods: We developed a suspension coculture system comprising breast cancer cells and macrophages and used RT-qPCR and western blotting to measure KDM6B expression. Bioinformatics and luciferase reporter assays were used to identify candidate microRNAs of cancer cells responsible for the downregulation of KDM6B. To determine if exosomes mediated the transfer of miR-138-5p between cancer cells to macrophages, we treated macrophages with exosomes collected from the conditioned medium of cancer cells. The effects of exosomal miR-138-5p on macrophage polarization were measured using RT-qPCR, flow cytometry, and chromatin immunoprecipitation assays. We employed a mouse model of breast cancer, metastatic to the lung, to evaluate the effects on tumor metastasis of macrophages treated with miR-138-5p-enriched exosomes. To develop a diagnostic evaluation index, the levels of exosomal miR-138-5p in samples from patients with breast cancer were compared to those of controls. Results: Coculture of breast cancer cells led to downregulation of KDM6B expression in macrophages. Cancer cell-derived exosomal miR-138-5p inhibited M1 polarization and promoted M2 polarization through inhibition of KDM6B expression in macrophages. Macrophages treated with exosomal miR-138-5p promoted lung metastasis, and the level of circulating exosomal miR-138-5p positively correlated with the progression of breast cancer. Conclusion: Our data suggest that miR-138-5p was delivered from breast cancer cells to tumor-associated macrophages via exosomes to downregulate KDM6B expression, inhibit M1 polarization, and stimulate M2 polarization. Therefore, exosomal miR-138-5p represents a promising prognostic marker and target for the treatment of breast cancer.

GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice.

The homeostasis of protein palmitoylation and depalmitoylation is essential for proper physiological functions in various tissues, in particular the central nervous system (CNS). The dysfunction of PPT1 (PPT1-KI, infantile neuronal ceroid lipofuscinosis [INCL] mouse model), which catalyze the depalmitoylation process, results in serious neurodegeneration accompanied by severe astrogliosis in the brain. Endeavoring to determine critical factors that might account for the pathogenesis in CNS by palm-proteomics, glial fibrillary acidic protein (GFAP) was spotted, indicating that GFAP is probably palmitoylated. Questions concerning if GFAP is indeed palmitoylated in vivo and how palmitoylation of GFAP might participate in neural pathology remain unexplored and are waiting to be investigated. Here we show that GFAP is readily palmitoylated in vitro and in vivo; specifically, cysteine-291 is the unique palmitoylated residue in GFAP. Interestingly, it was found that palmitoylated GFAP promotes astrocyte proliferation in vitro. Furthermore, we showed that PPT1 depalmitoylates GFAP, and the level of palmitoylated GFAP is overwhelmingly up-regulated in PPT1-knockin mice, which lead us to speculate that the elevated level of palmitoylated GFAP might accelerate astrocyte proliferation in vivo and ultimately led to astrogliosis in INCL. Indeed, blocking palmitoylation by mutating cysteine-291 into alanine in GFAP attenuate astrogliosis, and remarkably, the concurrent neurodegenerative pathology in PPT1-knockin mice. Together, these findings demonstrate that hyperpalmitoylated GFAP plays critical roles in regulating the pathogenesis of astrogliosis and neurodegeneration in the CNS, and most importantly, pinpointing that cysteine-291 in GFAP might be a valuable pharmaceutical target for treating INCL and other potential neurodegenerative diseases.

Legumain promotes tubular ferroptosis by facilitating chaperone-mediated autophagy of GPX4 in AKI.

Legumain is required for maintenance of normal kidney homeostasis. However, its role in acute kidney injury (AKI) is still unclear. Here, we induced AKI by bilateral ischemia-reperfusion injury (IRI) of renal arteries or folic acid in lgmnWT and lgmnKO mice. We assessed serum creatinine, blood urea nitrogen, histological indexes of tubular injury, and expression of KIM-1 and NGAL. Inflammatory infiltration was evaluated by immunohistological staining of CD3 and F4/80, and expression of TNF-α, CCL-2, IL-33, and IL-1α. Ferroptosis was evaluated by Acsl4, Cox-2, reactive oxygen species (ROS) indexes H2DCFDA and DHE, MDA and glutathione peroxidase 4 (GPX4). We induced ferroptosis by hypoxia or erastin in primary mouse renal tubular epithelial cells (mRTECs). Cellular survival, Acsl4, Cox-2, LDH release, ROS, and MDA levels were measured. We analyzed the degradation of GPX4 through inhibition of proteasomes or autophagy. Lysosomal GPX4 was assessed to determine GPX4 degradation pathway. Immunoprecipitation (IP) was used to determine the interactions between legumain, GPX4, HSC70, and HSP90. For tentative treatment, RR-11a was administrated intraperitoneally to a mouse model of IRI-induced AKI. Our results showed that legumain deficiency attenuated acute tubular injury, inflammation, and ferroptosis in either IRI or folic acid-induced AKI model. Ferroptosis induced by hypoxia or erastin was dampened in lgmnKO mRTECs compared with lgmnWT control. Deficiency of legumain prevented chaperone-mediated autophagy of GPX4. Results of IP suggested interactions between legumain, HSC70, HSP90, and GPX4. Administration of RR-11a ameliorated ferroptosis and renal injury in the AKI model. Together, our data indicate that legumain promotes chaperone-mediated autophagy of GPX4 therefore facilitates tubular ferroptosis in AKI.

SIRT7-dependent deacetylation of NPM promotes p53 stabilization following UV-induced genotoxic stress.

Adaptation to different forms of environmental stress is crucial for maintaining essential cellular functions and survival. The nucleolus plays a decisive role as a signaling hub for coordinating cellular responses to various extrinsic and intrinsic cues. p53 levels are normally kept low in unstressed cells, mainly due to E3 ubiquitin ligase MDM2-mediated degradation. Under stress, nucleophosmin (NPM) relocates from the nucleolus to the nucleoplasm and binds MDM2, thereby preventing degradation of p53 and allowing cell-cycle arrest and DNA repair. Here, we demonstrate that the mammalian sirtuin SIRT7 is an essential component for the regulation of p53 stability during stress responses induced by ultraviolet (UV) irradiation. The catalytic activity of SIRT7 is substantially increased upon UV irradiation through ataxia telangiectasia mutated and Rad3 related (ATR)-mediated phosphorylation, which promotes efficient deacetylation of the SIRT7 target NPM. Deacetylation is required for stress-dependent relocation of NPM into the nucleoplasm and MDM2 binding, thereby preventing ubiquitination and degradation of p53. In the absence of SIRT7, stress-dependent stabilization of p53 is abrogated, both in vitro and in vivo, impairing cellular stress responses. The study uncovers an essential SIRT7-dependent mechanism for stabilization of the tumor suppressor p53 in response to genotoxic stress.

FZR1 as a novel biomarker for breast cancer neoadjuvant chemotherapy prediction.

The concept of breast-conserving surgery is a remarkable achievement of breast cancer therapy. Neoadjuvant chemotherapy is being used increasingly to shrink the tumor prior to surgery. Neoadjuvant chemotherapy is reducing the tumor size to make the surgery with less damaging to surrounding tissue and downstage locally inoperable disease to operable. However, non-effective neoadjuvant chemotherapy could increase the risks of delaying surgery, develop unresectable disease and metastatic tumor spread. The biomarkers for predicting the neoadjuvant chemotherapy effect are scarce in breast cancer treatment. In this study, we identified that FZR1 can be a novel biomarker for breast cancer neoadjuvant chemotherapy according to clinical patient cohort evaluation and molecular mechanism investigation. Transcriptomic data analysis indicated that the expression of FZR1 is correlated with the effect of neoadjuvant chemotherapy. Mechanistically, we demonstrate that FZR1 is pivotal to the chemotherapy drugs induced apoptosis and cell cycle arrest. FZR1 is involved in the stability of p53 by impairing the phosphorylation at ser15 site. We demonstrate that the expression of FZR1 detected by quantification of IHC can be an effective predictor of neoadjuvant chemotherapy in animal experiment and clinical patient cohort. To obtain more benefit for breast cancer patient, we propose that the FZR1 IHC score using at the clinical to predict the effect of neoadjuvant chemotherapy.

MGAT3-mediated glycosylation of tetraspanin CD82 at asparagine 157 suppresses ovarian cancer metastasis by inhibiting the integrin signaling pathway.

Background: Tetraspanins constitute a family of transmembrane spanning proteins that function mainly by organizing the plasma membrane into micro-domains. CD82, a member of tetraspanins, is a potent inhibitor of cancer metastasis in numerous malignancies. CD82 is a highly glycosylated protein, however, it is still unknown whether and how this post-translational modification affects CD82 function and cancer metastasis. Methods: The glycosylation of CD82 profiles are checked in the paired human ovarian primary and metastatic cancer tissues. The functional studies on the various glycosylation sites of CD82 are performed in vitro and in vivo. Results: We demonstrate that CD82 glycosylation at Asn157 is necessary for CD82-mediated inhibition of ovarian cancer cells migration and metastasis in vitro and in vivo. Mechanistically, we discover that CD82 glycosylation is pivotal to disrupt integrin α5ß1-mediated cellular adhesion to the abundant extracellular matrix protein fibronectin. Thereby the glycosylated CD82 inhibits the integrin signaling pathway responsible for the induction of the cytoskeleton rearrangements required for cellular migration. Furthermore, we reveal that the glycosyltransferase MGAT3 is responsible for CD82 glycosylation in ovarian cancer cells. Metastatic ovarian cancers express reduced levels of MGAT3 which in turn may result in impaired CD82 glycosylation. Conclusions: Our work implicates a pathway for ovarian cancers metastasis regulation via MGAT3 mediated glycosylation of tetraspanin CD82 at asparagine 157.

Legumain-deficient macrophages promote senescence of tumor cells by sustaining JAK1/STAT1 activation.

Macrophages serve as the first line of communication between tumors and the rest of the immune system, and understanding the interplay between macrophage and tumor cells is essential for developing novel macrophage-based strategy against tumor. Here, we show that deletion of legumain in macrophages activates senescence of tumor cells. Macrophage derived IL-1ß mediates the pro-senescent effect of Lgmn-/- macrophages since blockage of IL-1ß reverses the senescence phenotype in both a coculture model of macrophage and tumor cells and an orthotopic mouse model of breast cancer. Sustained activation of JAK1/STAT1 signaling and increased iNOS were found in the tumor cell-cocultured Lgmn-/- macrophages, which were necessary for IL-1ß expression and secretion. Applying a specific STAT1 agonist mimics the inductive effect of legumain deletion on IL-1ß expression in macrophages, and the effect can be blocked via inhibition of iNOS. Legumain and integrin αvß3 interact to prevent STAT1 signaling in macrophages, and blockage of integrin αvß3 stimulates STAT1 activation. Therapeutically, transplantation of bone marrow from Lgmn-/- mice suppresses the malignant growth of tumor by upregulating tumor cell senescence. Therefore, our finding highlights legumain in macrophages as a potential therapeutic target for tumors.

Illumination of cell cycle progression by multi-fluorescent sensing system.

Multi-fluorescent imaging of cell cycle progression is essential for the study of cell proliferation in vitro and in vivo. However, there remain challenges, particularly to image cell cycle progression in living cell with available imaging techniques due to lacking the suitable probe. Here, we design a triple fluorescent sensors system making the cell cycle progression visible. Multi-fluorescent sensor shows the proliferating or proliferated cells with different colors. We thus generate the construct and adenovirus to probe cell cycle progression in living cell lines and primary cardiomyocytes. Furthermore, we create the knock-in transgenic mouse to monitor cell cycle progression in vivo. Together, the system can be applied to investigate cell proliferation or cell cycle progression in living cells and animals.

Distorted leukocyte migration, angiogenesis, wound repair and metastasis in Tspan8 and Tspan8/CD151 double knockout mice indicate complementary activities of Tspan8 and CD51.

The tetraspanin Tspan8 supports via associated integrins and proteases tumor progression and angiogenesis. To shed light on its activities in non-transformed cells, we generated a Tspan8 knockout (ko) mouse, comparing leukocyte migration, angiogenesis, wound healing and tumor growth with wild type, CD151ko and Tspan8/CD151ko (dbko) mice. CD151ko mice were included as CD151 activities resemble that of Tspan8, and dbko mice to exclude mutual substitution. Tspan8ko and dbko mice show no pathological phenotype. However, delayed type hypersensitivity reactions are mitigated in Tspan8ko mice, angiogenesis is severely impaired in Tspan8ko, CD151ko and dbko mice, with Tspan8 mostly affecting lymphangiogenesis. Distinct contributions of CD151 and Tspan8 to skin wound healing rely on preferentially CD151 anchoring basal keratinocytes and Tspan8 promoting motility. Proliferation of wounded skin keratinocytes is not affected. Metastasis formation of a melanoma and a Tspan8-expressing pancreatic cancer line was impaired in Tspan8ko and dbko mice, pointing towards a contribution of host Tspan8 to tumor progression. In line with the importance of tetraspanins in exosome-mediated intercellular communication, defects became mitigated by Tspan8/CD151-competent serum exosomes, which offers a most promising therapeutic option for chronic wounds and arteriosclerosis.

Exosomal tetraspanins mediate cancer metastasis by altering host microenvironment.

The metastases of malignant tumors develop through a cascade of events. The establishment of a pre-metastatic micro-environment is initiated by communication between tumors and host. Exosomes come into focus as the most potent intercellular communicators playing a pivotal role in this process. Cancer cells release exosomes into the extracellular environment prior to metastasis. Tetraspanin is a type of 4 times transmembrane proteins. It may be involved in cell motility, adhesion, morphogenesis, as well as cell and vesicular membrane fusion. The exosomal tetraspanin network is a molecular scaffold connecting various proteins for signaling transduction. The complex of tetraspanin-integrin determines the recruiting cancer exosomes to pre-metastatic sites. Tetraspanin is a key element for the target cell selection of exosomes uptake that may lead to the reprogramming of target cells. Reprogrammed target cells assist pre-metastatic niche formation. Previous reviews have described the biogenesis, secretion and intercellular interaction of exosomes in various tumors. However, there is a lack of reviews on the topic of exosomal tetraspanin in the context of cancer. In this review, we will describe the main characteristics of exosomal tetraspanin in cancer cells. We will also discuss how the cancer exosomal tetraspanin alters extracellular environment and regulates cancer metastasis.

Joint features and complementarities of Tspan8 and CD151 revealed in knockdown and knockout models.

Tetraspanins are highly conserved 4-transmembrane proteins which form molecular clusters with a large variety of transmembrane and cytosolic proteins. By these associations tetraspanins are engaged in a multitude of biological processes. Furthermore, tetraspanin complexes are located in specialized microdomains, called tetraspanin-enriched microdomains (TEMs). TEMs provide a signaling platform and are poised for invagination and vesicle formation. These vesicles can be released as exosomes (Exo) and are important in cell contact-independent intercellular communication. Here, we summarize emphasizing knockdown and knockout models' pathophysiological joint and selective activities of CD151 and Tspan8, and discuss the TEM-related engagement of CD151 and Tspan8 in Exo activities.