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Integrins have been extensively investigated as therapeutic targets over the last decades, which has been inspired by their multiple functions in cancer progression, metastasis, and angiogenesis as well as a continuously expanding number of other diseases, e.g., sepsis, fibrosis, and viral infections, possibly also Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Although integrin-targeted (cancer) therapy trials did not meet the high expectations yet, integrins are still valid and promising targets due to their elevated expression and surface accessibility on diseased cells. Thus, for the future successful clinical translation of integrin-targeted compounds, revisited and innovative treatment strategies have to be explored based on accumulated knowledge of integrin biology. For this, refined approaches are demanded aiming at alternative and improved preclinical models, optimized selectivity and pharmacological properties of integrin ligands, as well as more sophisticated treatment protocols considering dose fine-tuning of compounds. Moreover, integrin ligands exert high accuracy in disease monitoring as diagnostic molecular imaging tools, enabling patient selection for individualized integrin-targeted therapy. The present review comprehensively analyzes the state-of-the-art knowledge on the roles of RGD-binding integrin subtypes in cancer and non-cancerous diseases and outlines the latest achievements in the design and development of synthetic ligands and their application in biomedical, translational, and molecular imaging approaches. Indeed, substantial progress has already been made, including advanced ligand designs, numerous elaborated pre-clinical and first-in-human studies, while the discovery of novel applications for integrin ligands remains to be explored.

Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions. Such transmembrane adhesion and signaling receptors are thus recognized as promising and well accessible targets for novel diagnostic and therapeutic applications for directly attacking cancer cells and their fatal microenvironment. Recently, specific small peptidic and peptidomimetic ligands as well as antibodies binding to distinct integrin subtypes have been developed and synthesized as new drug candidates for cancer treatment. Understanding the distinct functions and interplay of integrin subtypes is a prerequisite for selective intervention in integrin-mediated diseases. Integrin subtype-specific ligands labelled with radioisotopes or fluorescent molecules allows the characterization of the integrin patterns in vivo and later the medical intervention via subtype specific drugs. The coating of nanoparticles, larger proteins, or encapsulating agents by integrin ligands are being explored to guide cytotoxic reagents directly to the cancer cell surface. These ligands are currently under investigation in clinical studies for their efficacy in interference with tumor cell adhesion, migration/invasion, proliferation, signaling, and survival, opening new treatment approaches in personalized medicine.

Tumors utilize a number of effective strategies, including the programmed death 1/PD ligand 1 (PD-1/PD-L1) axis, to evade immune-mediated control of their growth. PD-L1 expression is mainly induced by IFN receptor signaling or constitutively induced. Integrins are an abundantly expressed class of proteins which play multiple deleterious roles in cancer and exert proangiogenic and prosurvival activities. We asked whether αvβ3-integrin positively regulates PD-L1 expression and the anticancer immune response. We report that αvβ3-integrin regulated constitutive and IFN-induced PD-L1 expression in human and murine cancerous and noncancerous cells. αvβ3-integrin targeted STAT1 through its signaling C tail. The implantation of β3-integrin–depleted tumor cells led to a dramatic decrease in the growth of primary tumors, which exhibited reduced PD-L1 expression and became immunologically hot, with increased IFNγ content and CD8+ cell infiltration. In addition, the implantation of β3-integrin–depleted tumors elicited an abscopal immunotherapeutic effect measured as protection from the challenge tumor and durable splenocyte and serum reactivity to B16 cell antigens. These modifications to the immunosuppressive microenvironment primed cells for checkpoint (CP) blockade. When combined with anti–PD-1, β3-integrin depletion led to durable therapy and elicited an abscopal immunotherapeutic effect. We conclude that in addition to its previously known roles, αvβ3-integrin serves as a critical component of the cancer immune evasion strategy and can be an effective immunotherapy target.

Multimeric ligands consisting of multiple pharmacophores connected to a single backbone have been widely investigated for diagnostic and therapeutic applications. In this review, we summarize recent developments regarding multimeric radioligands targeting integrin αvβ3 receptors on cancer cells for molecular imaging and diagnostic applications using positron emission tomography (PET). Integrin αvβ3 receptors are glycoproteins expressed on the cell surface, which have a significant role in tumor angiogenesis. They act as receptors for several extracellular matrix proteins exposing the tripeptide sequence arginine-glycine-aspartic (RGD). Cyclic RDG peptidic ligands c(RGD) have been developed for integrin αvβ3 tumor-targeting positron emission tomography (PET) diagnosis. Several c(RGD) pharmacophores, connected with the linker and conjugated to a chelator or precursor for radiolabeling with different PET radionuclides (18F, 64Cu, and 68Ga), have resulted in multimeric ligands superior to c(RGD) monomers. The binding avidity, pharmacodynamic, and PET imaging properties of these multimeric c(RGD) radioligands, in relation to their structural characteristics are analyzed and discussed. Furthermore, specific examples from preclinical studies and clinical investigations are included.

The urokinase‐type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR ‐(s)uPAR‐ from circulation) is to regulate podocyte function through αvβ3 integrin/Rac‐1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors (FPRs) can improve kidney lesions in a rat model of streptozotocin (STZ)‐induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, αvβ3 integrin/Rac‐1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ‐induced up‐regulation of uPA levels and activity, while uPAR on podocytes and (s)uPAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the αvβ3 integrin/Rac‐1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen‐plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/uPAR system as a promising target for the development of novel uPAR‐targeting approaches.

Background Interleukin-8 (IL-8) plays a vital role in the invasion and metastasis of hepatocellular carcinoma (HCC), and is closely associated with poor prognosis of HCC patients. Integrin αvβ3, a member of the integrin family, has been reported to be overexpressed in cancer tissues and mediate the invasion and metastasis of HCC cells. However, the relationship between IL-8 and integrin αvβ3 in HCC and the underlying mechanism of IL-8 and integrin αvβ3 in the invasion of HCC remains unclear. Methods The expression of IL-8, integrin αv and integrin β3 in HCC cells and tissues was detected by quantitative real-time PCR, Western blot and immunohistochemistry. Transwell assay and Western blot was used to detect the invasiveness, the expression of integrin β3 and the activation of PI3K/Akt pathway of HCC cells pretreated with IL-8 knockdown or exogenous IL-8. Results IL-8, integrin αv and integrin β3 were overexpressed in highly metastatic HCC cell lines compared with low metastatic cell lines. There was a positive correlation between integrin β3 and IL-8 expression in HCC tissues. IL-8 siRNA transfection reduced HCC cell invasion and the levels of integrin β3, p-PI3K and p-Akt. IL-8 induced HCC cell invasion and integrin β3 expression was significantly inhibited by transfection with CXCR1 siRNA or CXCR2 siRNA. When we stimulated HCC cells with exogenous IL-8, cell invasion and the levels of integrin β3, p-PI3K, and p-Akt increased, which could be effectively reversed by adding PI3K inhibitor LY294002. Conclusions Our results suggest that IL-8 promotes integrin β3 upregulation and the invasion of HCC cells through activation of the PI3K/Akt pathway. The IL-8/CXCR1/CXCR2/PI3K/Akt/integrin β3 axis may serve as a potential treatment target for patients with HCC.

[This corrects the article DOI: 10.3389/fphar.2019.01373.].

Breast cancer is a heterogeneous disease that is characterized by a high grade of cell plasticity arising from the contribution of a diverse range of factors. When combined, these factors allow a cancer cell to transition from an epithelial to a mesenchymal state through a process of dedifferentiation that confers stem-like features, including chemoresistance, as well as the capacity to migrate and invade. Understanding the complex events that lead to the acquisition of a mesenchymal phenotype will therefore help to design new therapies against metastatic breast cancer. Here, we recapitulate the main endogenous molecular signals involved in this process, and their cross-talk with paracrine factors. These signals and cross-talk include the extracellular matrix; the secretome of cancer-associated fibroblasts, macrophages, cancer stem cells, and cancer cells; and exosomes with their cargo of miRNAs. Finally, we highlight some of the more promising therapeutic perspectives based on counteracting the epithelial-to-mesenchymal transition in breast cancer cells.

To enhance tumor uptake and retention, we designed and developed bi-specific heterodimeric radiotracers targeting both FAP and αvβ3, [ Ga]Ga-FAPI-RGD. The present study aimed to evaluate the specificity, pharmacokinetics, and dosimetry of [ Ga]Ga-FAPI-RGD by preclinical and preliminary clinical studies. FAPI-RGD was designed and synthesized with the quinoline-based FAPI-02 and the cyclic RGDfK peptide. Preclinical pharmacokinetics were determined in Panc02 xenograft model using microPET and biodistribution experiments. The safety and effective dosimetry of [ Ga]Ga-FAPI-RGD was evaluated in 6 cancer patients, and compared with 2-[ F]FDG imaging. The [ Ga]Ga-FAPI-RGD had good stability in saline for at least 4 h, and showed favorable binding affinity and specificity and . Compared to [ Ga]Ga-FAPI-02 and [ Ga]Ga-RGDfK, the tumor uptake and retention of [ Ga]Ga-FAPI-RGD were very much enhanced than its monomeric counterparts at all the time points examined by microPET imaging. A total of 6 patients with various malignant tumors were prospectively enrolled. The effective dose of [ Ga]Ga-FAPI-RGD was 1.94E-02 mSv/MBq. The biodistribution of [ Ga]Ga-FAPI-RGD from 0 to 2 h after injection demonstrated rapid and high tumor uptake, prolonged tumor retention, and high tumor-to-background ratios (TBRs) which further increased over time. No significant difference in mean SUVmax of [ Ga]Ga-FAPI-RGD and 2-[ F]FDG was present in primary tumors (8.9±3.2 10.3 ± 6.9; p = 0.459). The dual targeting PET tracer [ Ga]Ga-FAPI-RGD showed significantly improved tumor uptake and retention, as well as cleaner background over Ga-labeled FAPI and RGD monospecific tracers. The first-in-human biodistribution study showed high TBRs over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.

Shikonin (SHK) has been proven to have a good anti-tumor effect. However, poor water solubility and low bioavailability limit its wide application in clinical practice. In this study, to overcome these drawbacks, RGD-modified shikonin-loaded liposomes (RGD-SSLs-SHK) were successfully prepared. It exhibited excellent physicochemical characteristics including particle size, zeta potential, encapsulation efficiency, and delayed release time. Meanwhile, the targeting activity of the RGD-modified liposomes was demonstrated by flow cytometry and confocal microscopy in the αvβ3-positive MDA-MB-231 cells. Besides exhibiting greater cytotoxicity in vitro, compared with non-targeted shikonin-loaded liposomes (SSLs-SHK), RGD-SSLs-SHK could also evidently induce apoptosis by decreasing the expression of Bcl-2 and increasing the expression of Bax. It could also inhibit cell proliferation, migration, invasion, and adhesion by reducing the expression of MMP-9 and the level of NF-κB p65, but did not affect the expression of MMP-2 in the MDA-MB-231 cells. Therefore, these findings indicated that the strategy to use RGD-modified liposomes as carriers for targeted delivery of shikonin is a very promising approach to achieve breast cancer targeted therapy.