Integrins are important cell surface adhesion receptors that bind to both extracellular matrix (ECM) ligands and cell surface ligands (1). As pivotal signaling molecules, integrins mediate cell migration and adhesion (2,3). Previous reports have shown that integrins are highly expressed in a variety of cancer types including lung cancer, hepatocellular carcinoma, pancreatic cancer and head and neck squamous cell carcinomas, and serve crucial roles in nearly every stage of cancer progression, including the initiation of primary tumor formation, subsequent growth and the metastatic cascade (4-8). Integrin-mediated sensing, stiffening and remodeling of the tumor stroma are key steps in supporting tumor cell invasion, acquiring cancer stem cell (CSC) characteristics and developing drug resistance during cancer progression (9,10). In addition, integrins have emerged as attractive targets for both predicting cancer prognosis and devising therapeutic strategies (11). Several integrin inhibitors, which disrupt the interaction between integrins and their respective ligands, hold notable therapeutic promise (12).

Exosomes are extracellular vesicles (EVs) secreted by cells, which serve a crucial role in regulating intercellular transport. Specifically, exosomes influence the state of both adjacent and distant cells by delivering nucleic acids, proteins and lipids (13). Tumor-derived exosomes (TDEs) are particularly important in angiogenesis, immune system regulation and the remodeling of surrounding tissues, thereby supporting tumor progression and metastasis to organs (14). As intercellular messengers, exosomes reflect the physiological state of various tumor cells, thus serving as biomarkers for clinical diagnosis and evaluation (15). Integrins have been identified as important components of exosomes. Accumulating evidence indicates that exosomal integrins assist in exosome homing, signal transduction and the phenotypic transformation of recipient cells (16-18). Research on exosomes and integrins has been steadily advancing. However, there remains a lack of comprehensive reviews summarizing the role of exosomal integrins in tumor development. Exploring the role of exosomal integrins in tumors will enhance the understanding of tumor pathogenesis and help to identify new diagnostic and therapeutic strategies (10). In the present review, the roles of exosomal integrins in tumor migration, tumorigenesis [including epithelial-mesenchymal transition (EMT)], angiogenesis, formation of the pre-metastatic niche (PMN) and the development of tumor drug resistance were summarized. Additionally, the potential of exosomal integrins in tumor prediction and treatment were examined, which highlighted their prospects in improving the efficiency of these aspects.

Cells release various types of EVs, including exosomes, microvesicles and apoptotic bodies. Exosomes are the smallest entities among EVs, with a diameter ranging 40-160 nm (average, ~100 nm), are secreted by almost all cell types and have been found in all biological fluids (19). The contents of exosomes vary and reflect the composition of the donor cells (20,21). Exosomes contain adhesion molecules, tetraspanins, major histocompatibility complex molecules, transmembrane proteins, cytosolic (such as heat shock proteins, cytoskeletal proteins and transporters) and nuclear proteins, lipids, nucleic acids (including DNA, mRNA and non-coding RNAs), amino acids and metabolites (such as bioactive lipids, glycosidases and nucleotides) (Fig. 1) (22,23).

The formation and secretion of exosomes is a complex process, which is typically divided into two pathways: The endosomal sorting complex required for transport (ESCRT)-dependent pathway and the ESCRT-independent pathway (24). The ESCRT system is a molecular machine that completes endosomal membrane invagination to form multivesicular bodies (MVBs) in eukaryotic cells. The ESCRT-dependent pathway involves a series of complexes such as ESCRT-0, -I, -II and -III (25). ESCRT-0 is responsible for the recognition of mono-ubiquitinated proteins. Then, ESCRT-I and -II bind to ESCRT-0 to induce endosomal membrane budding. Finally, ESCRT-Ⅲ aggregates at the bud neck to pinch off the membrane, thereby releasing intraluminal vesicles (ILVs) into the lumen to form the MVBs (24,26). This process includes three steps: i) Extracellular substances, such as lipids, proteins and metabolites, enter cells through the initial plasma membrane invagination to form early-sorting endosomes (ESEs); ii) ESEs mature into late-sorting endosomes and then form MVBs. MVBs contain ILVs regulated by the ESCRT complex, which are the precursors to exosomes; and iii) MVBs either fuse with the plasma membrane to release exosomes or merge with autophagosomes and are degraded in the lysosomes (Fig. 1) (23,27). Studies have shown that, after the components of the ESCRT complex are depleted, exosome production is not completely blocked and a small number of exosomes are still formed (28,29). This suggests that exosomes can form in a manner independent of the ESCRT pathway. In the ESCRT-independent mechanism, the release of exosomes is dependent on sphingomyelinase. This involves the hydrolysis process of sphingomyelins into ceramides via neutral sphingomyelinase, which promotes inward budding of vesicles (30).

Exosomes carry a variety of bioactive molecules that have key roles in physiological and pathological processes through precise and dynamic intercellular communication. These processes include immune responses and infections, metabolic diseases, cardiovascular diseases, neurodegenerative diseases and cancer (31,32). Particularly, exosomes have gained attention in the field of cancer biology. Exosomes alter the fate of both the recipient and exosome-releasing cells through autocrine and paracrine signaling pathways (33). TDEs affect tumor growth, metastasis and drug resistance by interacting with tumor and stromal cells (34). Tumor stromal cells are primarily cancer-associated fibroblasts (CAFs) and immune cells (35). Exosomes have been recognized as crucial mediators in regulating the extracellular communication and metabolic reprogramming between CAFs and cancer cells (36,37). Furthermore, TDEs remodel the distant microenvironment at metastatic sites via blood and lymphatic circulation (38). Accumulating evidence indicates that TDEs are associated with angiogenesis and ECM remodeling in the tumor microenvironment (TME) (39-41).

Integrins are cell adhesion molecules that serve as membrane protein complexes, linking the ECM to the cytoskeleton, and regulate various cell behaviors, such as adhesion, proliferation and apoptosis, by triggering signal transduction through their extracellular connections to the cytoskeleton. This regulation provides the impetus and direction for cell migration and invasion (42,43). Integrins are ubiquitous in mammals, chickens, zebrafish and lower eukaryotes (44). In mammals, integrins are composed of α and β subunits bound by non-covalent bonds. To date, 18 α subunits and 8 β subunits have been identified, forming 24 αβ heterodimeric integrins with different properties and tissue distributions based on the various combinations. Both the α and β subunits are type I transmembrane proteins, each containing ectodomains, transmembrane domains and cytoplasmic domains (45,46). The integrin ectodomains are responsible for interacting with integrin ligands of the ECM (47). Due to the different characteristics of the integrin-ligand combinations, integrins can be clustered into four classes: Arginine-glycine-aspartate (RGD)-binding integrins (including αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α5β1, α8β1 and αIIbβ3) (48), leukocyte cell-adhesion integrins (including α4β1, α9β1, αLβ2, αMβ2, αXβ2, αDβ2, α4β7 and αEβ7) (49), collagen-binding integrins (which recognize the GFOGER binding site, including α1β1, α2β1, α10β1 and α11β1) (50) and laminin-binding integrins (including α3β1, α6β1, α6β4 and α7β1) (Fig. 2) (51,52).

Integrin-mediated transmembrane signals can exert their role through conformational transition. These transitions strictly regulate the transformation of integrins from a low-affinity state to a high-affinity state (53). Proteins such as talin, kindlin and tetraspanin trigger integrins to adopt an active open conformation, while integrin cytoplasmic domain-associated protein-1 and SHARPIN stabilize and inactivate integrins (54). Integrin-mediated transmembrane signals are bidirectional. During 'outside-in' signaling, integrins exposed to exosomes recognize and bind to their specific ligands on the surface of the target cells, generating intracellular signals. These signals control a series of physiological functions, including regulating cell polarity, altering the cytoskeleton structure, as well as cell survival and proliferation (55). The affinity of cells to extracellular ligands is regulated by 'inside-out' signaling. As this affinity increases, the interaction between integrins and the ECM becomes strong enough to induce cells to migrate and the ECM to remodel (Fig. 2) (56).

Integrins are expressed on the surface of tumor cells. The expression of integrins αvβ3, αvβ5, α5β1, α6β4, α4β1 and αvβ6 on tumor cells may have an important role in the progression of lung, breast, prostate, pancreatic and colorectal cancers (4,57). The abnormal expression of integrins is involved in almost every stage of cancer development, from the formation of primary tumors to the establishment of metastatic niches (9). During tumor cell survival and proliferation, integrin β1 promotes the survival of cancer cells by activating different cell signaling proteins and enhances cell proliferation by phosphorylating focal adhesion kinase (FAK) (58). Additionally, integrin αvβ3 enhances the migration and invasion of non-small cell lung cancer (NSCLC) cells by triggering the FAK signaling pathway (59). A specific integrin subtype, αvβ6, is expressed in some types of malignant tumors, such as prostate, breast, colorectal and lung cancers, but not in normal epithelial cells or benign tumors (60). Furthermore, αvβ6 confers an invasive/metastatic phenotype to early colorectal cancer cells, promoting tumor metastasis and reducing patient survival (61). Integrins regulate the adhesion of tumor cells and the expression level of integrin is proportional to the adhesion (62). In the early stage of tumorigenesis, the expression of integrins is reduced, which is conducive to the growth and spread of tumors. Then, the tumor cells enter the blood circulation (63). Thereafter, the expression of integrin is increased, which is beneficial to the adhesion of tumor cells to the vascular endothelium. Specifically, integrins are the main adhesion molecule in the angiogenesis stage of tumorigenesis. Furthermore, integrins are expressed in the cavity and luminal surface of vascular endothelial cells, mediating endothelial cell migration and capillary lumen formation (64).

Exosomal integrins are a subset of integrins. Thus, cell membrane and exosomal integrins share similarities in that both are involved in cell-to-cell or cell-to-exosome communication. Currently, the understanding of the communication mechanism of exosomal integrins is still in its infancy. However, integrin function is considered to be regulated by talin in exosomes, as in other cellular systems (54). In addition to certain similarities in the communication mechanism, there are notable differences in the location and function of cell membrane and exosomal integrins (64,65). As aforementioned, cell membrane integrins mediate cell-ECM adhesion. In the occurrence, development and metastasis of tumors, this adhesion directly affects the physiological processes of tumor cell migration, proliferation and survival. By contrast, exosomal integrins are embedded in the membrane of exosomes, which are small EVs that promote intercellular communication. These exosomal integrins serve a crucial role in targeting specific cells or tissues to achieve long-term signal transduction in processes such as cancer metastasis and immune regulation (16,65). Exosomal integrins also serve an important role in directing the tissue distribution of exosomes, thereby supporting long-range cellular interactions (16,66). In addition, exosomal integrins are involved in multiple steps of tumor formation as they enhance cell adhesion and migration, participate in PMN formation, and they modulate angiogenesis (54). It has been reported that exosomal integrins also confer drug resistance to tumors and impair drug efficacy (67).

Exosomes have a notable influence on drug resistance, which is induced through a variety of mechanisms. During chemotherapy, cancer cells cannot remove exosomes containing unfavorable biomolecules. However, drug-resistant cancer cells can load chemotherapy drugs into exosomes and expel them from tumor cells directly (139,140). Another mechanism involves exosomes carrying a drug-resistant phenotype from drug-resistant cancer cells to drug-sensitive cancer cells (141). Additionally, exosomes can regulate the transfer of functional proteins and/or miRNAs, contributing to drug resistance (142). The contents of exosomes can also cause immunosuppression, leading to drug resistance in HER2+ breast cancer (143,144). Therefore, the roles of exosomes and integrins in drug resistance across different cancer types are reviewed here (Table I).

In drug-resistant human ovarian cancer, cisplatin (CDDP) is encapsulated in exosomes and released within the secretory pathway (145). The ATP-binding cassette (ABC) transporter superfamily, including ABCB1 [also known as P-glycoprotein (P-gp)], ABCC1 (also known as multidrug resistance protein 1) and ABCG2 (also known as breast cancer resistance protein), function as multidrug resistance efflux transporters. These transporters, located on the exosomal membrane, actively pump anticancer drugs out of cells, resulting in chemoresistance (146). P-gp, a key anticancer pump transporter, plays a notable role in drug resistance by retaining drug concentrations in tumor cells below the therapeutic levels after chemotherapy, rendering the treatment ineffective. This process may be mediated by exosomal integrin, which facilitate the intercellular transfer of P-gp from multidrug-resistant cells to drug-sensitive cells (147). Suppression of αvβ6 downregulated the levels of MDR1 gene mRNA and P-gp. In particular, β6 shRNA-mediated silencing of the αvβ6 gene markedly decreased drug efflux ability (148). In addition, the delivery mechanisms of exosomes carrying nucleic acids and proteins are closely related to tumor drug resistance. For instance, the content of exosomes from paclitaxel-resistant ovarian cancer cells, namely miR-1246, induces chemoresistance by inhibiting 3′UTR caveolin-1, which directly suppresses the increase of p-gp expression (149).

The effect of adhesion crosstalk between tumor cells and stromal cells on the development of tumor drug resistance has been studied in detail. Cancer cells adhere to the ECM or stromal cells and can avoid being killed by radiotherapy and chemotherapy, which is known as cell adhesion-mediated drug resistance (CAM-DR) (150). CAM-DR is determined by the integrin-ECM interaction. For instance, integrin β1 is considered essential for radiotherapy resistance in human head and neck cancer (151) and mediates cell adhesion to the ECM. The role of integrins in tumor drug resistance is primarily related to integrin-mediated signaling pathways (152). For instance, the integrin β1/Src/AKT signaling pathway serves a key role in acquiring resistance to epidermal growth factor receptor-targeted anticancer drugs, such as gefitinib and erlotinib, in lung cancer (153). In human glioblastoma, resistance to temozolomide is mainly due to integrin α5β1 downregulating the p53 pathway (154). In breast cancer cells, integrin αvβ3 and its mediated FAK/PI3K/AKT signaling pathway are involved in CDDP resistance (155). Additionally, integrin α6 serves a key role in cancer drug resistance by regulating the MAPK/ERK and PI3K/AKT signaling pathways (156). Finally, integrin β4 and vinculin in exosomes are associated with taxane resistance in PrCa (157).

Exosomes are natural nano-biological delivery systems with properties of stability, biocompatibility (endogenous origin) and the ability to cross various physiological barriers. These features make exosomes promising carriers for delivering several drugs and biomacromolecules for cancer therapy (158). For instance, loading exosomes with paclitaxel has indicated the potential for delivering multiple chemotherapeutics to treat drug-resistant cancer (159). In cancer treatment, exosomes protect the integrity of nucleic acids and shield proteins from various enzymes and the immune system, making them excellent carriers for delivering these macromolecules in therapy. Kobayashi et al (160) demonstrated that loading miR-199a-3p into exosomes inhibited c-Met expression and reduced ovarian cancer cell proliferation, invasiveness and dissemination. Similarly, exosomes loaded with signal regulatory protein α (SIRPα) block the CD47 receptor on tumor cells more effectively when compared with ferritin-SIRPα, indicating that these exosomes have antitumor applications (161). In addition, since TDEs carry specific integrins on their surface, they ensure targeted delivery to specific organs and tissues. Exosome targeting was also accomplished by genetic modification of exosome donor cells (162). This characteristic enhances the accuracy and efficiency of delivering therapeutic contents through exosomes and exosomal integrins compared with other biological carriers (163). However, to meet the demands of large-scale clinical applications, the loading capacity and methods for exosomes require optimization.

The diagnosis of cancer is often invasive. However, non-invasive diagnostic methods in clinical oncology have emerged as feasible alternatives with the study of exosomes (164,165). Exosomes, which represent their source cells, contain biological information and are steadily secreted into body fluids, making them ideal specimens for liquid biopsy. More specifically, cancer biomarkers can be determined according to the characteristics of TDE contents (such as the proteins and nucleic acids) in blood, ascites or urine, as these exosomes contain information related to cancer progression (166). A study has shown that integrin β4 and vinculin levels in exosomes isolated from PC3 cells can serve as effective biomarkers for diagnosing PrCa associated with taxane resistance (157). The presence of integrin α2β1 in exosomes from tumor metastatic cells, but not in exosomes from non-cancerous WI-38 lung fibroblasts or epithelial MCF10A cells, indicates that this integrin can be regarded as a biomarker of metastasis (16).

Integrins have are promising, yet challenging, targets for the treatment of cancer. The specific expression of integrins in TDEs allows them to be used for disease monitoring, predicting patient survival and potentially distinguishing between cancer types and stages (167-169). For instance, integrin αvβ6, which is not expressed in normal adult epithelial cells but is present in cancer cells, can be utilized for the diagnosis and treatment of certain cancers such as ovarian, pancreatic, esophageal, bile duct, oral and cervical cancers (170). In mouse models, heavy lead peptides combined with αvβ6 have been used for non-invasive imaging, highlighting the potential of αvβ6 as a promising biomarker (171). Additionally, a patent states that the monoclonal antibody, 10D5, which specifically binds to β6, can be used to treat cancer (172). Invasive diagnostic techniques for multiple brain metastasis are often impractical in clinical settings, making it attractive to evaluate circulating EVs and related integrins as biomarkers. Experts isolated and quantified exosomal integrins of 75 patients with lung cancer with brain metastasis and analyzed the association of exosomal integrins with clinical factors, survival and intracranial or extracranial failure. Accordingly, it was proposed that integrin β3 may serve as a potential biomarker for the development of brain metastasis (137). Furthermore, the differential expression of exosomal integrins α6, αv and β1 is associated with the tumor stage of various epithelial cancers such as colon, lung, ovarian and prostate cancers (169).

Integrins are cell adhesion and signaling proteins present on the surface of various cell subsets, making them potential therapeutic targets. Numerous integrins involved in tumor progression have been studied as attractive therapeutic targets for cancer therapy (173,174). A study has shown that integrin antagonists, which currently include monoclonal antibodies, RGD peptide analogues and non-RGD antagonists, inhibit tumor growth by affecting tumor cells and tumor-associated host cells. For instance, integrin αvβ3 and αvβ5 inhibitors, such as cilengitide, have demonstrated this capability (132). Cilengitide can reduce the expression levels of integrin genes and inhibit the proliferation of tumor cells (175). In addition, cilengitide can activate αvβ3 and αvβ5 integrins of the FAK/Paxillin/AKT signaling pathway to combat chemotherapy resistance in glioblastoma (176). At present and to the best of our knowledge, there are seven drugs targeting integrins on the market: Abciximab, eptifibatide, tirofiban, natalizumab, vidolizumab, lifitegrast and carotegrast. However, drugs specifically targeting exosomal integrins have not yet been officially introduced to the market (52). The application of exosomes and integrins in cancer treatment and diagnosis is summarized in Table II.

The effectiveness of bodily fluid biopsy relies on advanced techniques for the isolation and characterization of exosomal integrins. Despite significant efforts in developing liquid biopsy methods and tumor biomarkers in oncology, only a few have progressed to the clinical stage. This is because clinical studies using liquid biopsy are often reliant on integrin content and heterogeneity, thereby rendering them more expensive and time-consuming compared with other common clinical testing techniques (177). To promote exosomal integrins as biomarkers to a broader population, more portable, efficient and accurate characterization techniques are needed (178). Standardization in the selection, separation, characterization, storage, management and quality control of exosomal integrins is crucial for their clinical application in tumor diagnosis and treatment. Most existing studies use tumor cell integrins as markers, but these are often affected by the complexity of tumors. Using specific integrins from TDEs in the humoral circulation as markers could reduce this interference.

Over the past 30 years, research on exosomal integrins as therapeutic targets has gained significant attention. However, most drugs have failed in phase III clinical trials, highlighting the challenges in translating experimental findings into clinical therapies (179). The pharmacodynamics and complex physiology of integrins contribute to the ongoing problems of toxicity and poor efficacy in drugs that have reached the market (180). Current treatment strategies mainly focus on interfering with integrin-ligand interactions. However, the class-specific nature of integrin-targeted therapy presents another challenge. Since the same integrin subunit can form different integrin heterodimers, the accuracy of targeted therapies is affected. Additionally, other molecules can interfere with targeted drugs. For instance, abciximab binds to both glycoprotein IIb/IIIa and integrin αvβ3 with a similar affinity, suggesting it may act as an antagonist of both GPIIb/IIIa and αvβ3 (181). Such complexities complicate the use of preclinical experimental data in developing effective therapies.

The heterodimeric structure of integrins enables them to specifically recognize amino-acid motifs. The binding of ligands to integrins can affect the allosteric states of integrins, thereby altering the movement of EVs. This suggests that exosomal integrins may act as sensors of the molecular environment. To effectively utilize exosomal integrins in cancer therapy, it is essential to fully understand their mechanisms of action in tumor development. Additionally, combining targeted drugs that act on ligands and integrins or their downstream effectors may offer a promising approach. This direction could lead to the development of new therapeutic strategies.