Integrin αvβ6: Structure, function and role in health and disease

Koivisto, Leeni; Bi, Jianping; Häkkinen, Lari; Larjava, Hannu

doi:10.1016/j.biocel.2018.04.013

Cited by 113 publications

(106 citation statements)

References 149 publications

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“…43 Notably, the observation of β 6 expression within endothelial cells is in line with data reporting α V β 6 expression in the epithelium from other tissues, such as lung, kidney, skin, enamel, and intestine. 44 Interestingly, integrin staining was also noticed on the external fibrous part of the blood vessels (i.e., "adventice"), which is consistent with the high mean expression score for integrin associated with this compartment. Indeed, all PRGD 2 -selective integrins show high mean expression scores in fibrous areas.…”

Section: Discussionsupporting

confidence: 74%

Toward diagnostic relevance of the αVβ5, αVβ3, and αVβ6 integrins in OA: expression within human cartilage and spinal osteophytes

et al. 2020

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We previously reported 18FPRGD2 uptake by the coxofemoral lining, intervertebral discs and facet joint osteophytes in OA using PET/SCAN imaging. However, the molecular mechanism by which the PRGD2 tracer interacts with joint tissues and osteophytes in OA remains unclear. As PRGD2 ligands are expected to belong to the RGD-specific integrin family, the purpose of this study was (i) to determine which integrin complexes display the highest affinity for PRGD2-based ligands, (ii) to analyze integrin expression in relevant tissues, and (iii) to test integrin regulation in chondrocytes using OA-related stimuli to increase the levels of fibrosis and ossification markers. To this end, the affinity of PRGD2-based ligands for five heterodimeric integrins was measured by competition with 125I-echistatin. In situ analyses were performed in human normal vs. OA cartilage and spinal osteophytes. Osteophytes were characterized by (immuno-)histological staining. Integrin subunit expression was tested in chondrocytes undergoing dedifferentiation, osteogenic differentiation, and inflammatory stimulation. The integrins αVβ5, αVβ3, and αVβ6 presented the highest affinity for PRGD2-based ligands. In situ, the expression of these integrins was significantly increased in OA compared to normal cartilage. Within osteophytes, the mean integrin expression score was significantly higher in blood vessels, fibrous areas, and cells from the bone lining than in osteocytes and cartilaginous zones. In vitro, the levels of integrin subunits were significantly increased during chondrocyte dedifferentiation (except for β6), fibrosis, and osteogenic differentiation as well as under inflammatory stimuli. In conclusion, anatomical zones (such as OA cartilage, intervertebral discs, and facet joint osteophytes) previously reported to show PRGD2 ligand uptake in vivo expressed increased levels of αVβ5, αVβ3, and β6 integrins, whose subunits are modulated in vitro by OA-associated conditions that increase fibrosis, inflammation, and osteogenic differentiation. These results suggest that the increased levels of integrins in OA compared to normal tissues favor PRGD2 uptake and might explain the molecular mechanism of OA imaging using the PRGD2-based ligand PET/CT.

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Section: Discussionsupporting

confidence: 74%

Toward diagnostic relevance of the αVβ5, αVβ3, and αVβ6 integrins in OA: expression within human cartilage and spinal osteophytes

et al. 2020

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“…There is increasing evidence of the important role of integrin a v b 6 in cancer, its suitability as a prognostic biomarker (linked to poor disease-free and overall survival), and the promise of an a v b 6 -targeted clinical diagnostic tool for in vivo detection, patient stratification, as well as monitoring of response to treatment (31)(32)(33). The high contrast in signal gained due to aberrant, but specific expression of a v b 6 suggests that a v b 6targeted agents have significant potential in the treatment and management of a multitude of malignancies.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Development and First-in-Human Imaging of the Integrin αvβ6 with [18F]αvβ6-Binding Peptide in Metastatic Carcinoma

Hausner

Bold

Cheuy

et al. 2019

Clinical Cancer Research

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Purpose: The study was undertaken to develop and evaluate the potential of an integrin a v b 6-binding peptide (a v b 6-BP) for noninvasive imaging of a diverse range of malignancies with PET. Experimental Design: The peptide a v b 6-BP was prepared on solid phase and radiolabeled with 4-[ 18 F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired a v b 6-expressing and a v b 6-null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired a v b 6-expressing and a v b 6-null cell xenografts. A first-inhuman PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer. Results: [ 18 F]a v b 6-BP displayed excellent affinity and selectivity for the integrin a v b 6 in vitro [IC 50 (a v b 6) ¼ 1.2 nmol/L vs IC 50 (a v b 3) >10 mmol/L] in addition to rapid target-specific cell binding and internalization (72.5% AE 0.9% binding and 52.5% AE 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [ 18 F]a v b 6-BP was rapid, primarily via the kidneys. In patients, [ 18 F]a v b 6-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [ 18 F]a v b 6-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung. Conclusions: The clinical impact of [ 18 F]a v b 6-BP PET imaging demonstrated in this first-inhuman study is immediate for a broad spectrum of malignancies.

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“…Several reports are in favor of optimizing the therapeutic benefit of ADSCs because of cytokine combination, including TGF-β and TNF-α. TGF-β was targeted by the integrin αβ6 and was secreted by the epithelial cells to modulate skin immune surveillance and the ADSC microenvironment [59]. The latter was dependent of IL-6 when initiating the inflammatory phase of wound healing.…”

Section: Role Of the Microenvironment In Adscs Inductionmentioning

confidence: 99%

“…These factors are consistently responsible for the inflammatory status of the immune skin cells and their impact on the nature and efficacy of healing is more appropriate by modulating the skin microenvironment, also suggesting the implication of ADSCs. TGF-β secreted by utmost skin epithelial cells regulated inflammatory responses via coordinating leukocytes infiltrations [59,153] and through NFkB and SMAD mechanism pathways [154].…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Hopes and Limits of Adipose-Derived Stem Cells (ADSCs) and Mesenchymal Stem Cells (MSCs) in Wound Healing

Mazini

Rochette

Admou

et al. 2020

IJMS

346

219

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Adipose tissue derived stem cells (ADSCs) are mesenchymal stem cells identified within subcutaneous tissue at the base of the hair follicle (dermal papilla cells), in the dermal sheets (dermal sheet cells), in interfollicular dermis, and in the hypodermis tissue. These cells are expected to play a major role in regulating skin regeneration and aging-associated morphologic disgraces and structural deficits. ADSCs are known to proliferate and differentiate into skin cells to repair damaged or dead cells, but also act by an autocrine and paracrine pathway to activate cell regeneration and the healing process. During wound healing, ADSCs have a great ability in migration to be recruited rapidly into wounded sites added to their differentiation towards dermal fibroblasts (DF), endothelial cells, and keratinocytes. Additionally, ADSCs and DFs are the major sources of the extracellular matrix (ECM) proteins involved in maintaining skin structure and function. Their interactions with skin cells are involved in regulating skin homeostasis and during healing. The evidence suggests that their secretomes ensure: (i) The change in macrophages inflammatory phenotype implicated in the inflammatory phase, (ii) the formation of new blood vessels, thus promoting angiogenesis by increasing endothelial cell differentiation and cell migration, and (iii) the formation of granulation tissues, skin cells, and ECM production, whereby proliferation and remodeling phases occur. These characteristics would be beneficial to therapeutic strategies in wound healing and skin aging and have driven more insights in many clinical investigations. Additionally, it was recently presented as the tool key in the new free-cell therapy in regenerative medicine. Nevertheless, ADSCs fulfill the general accepted criteria for cell-based therapies, but still need further investigations into their efficiency, taking into consideration the host-environment and patient-associated factors.

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Integrin αvβ6: Structure, function and role in health and disease

Cited by 113 publications

References 149 publications

Toward diagnostic relevance of the αVβ5, αVβ3, and αVβ6 integrins in OA: expression within human cartilage and spinal osteophytes

Toward diagnostic relevance of the αVβ5, αVβ3, and αVβ6 integrins in OA: expression within human cartilage and spinal osteophytes

Preclinical Development and First-in-Human Imaging of the Integrin αvβ6 with [18F]αvβ6-Binding Peptide in Metastatic Carcinoma

Hopes and Limits of Adipose-Derived Stem Cells (ADSCs) and Mesenchymal Stem Cells (MSCs) in Wound Healing

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