Integrin αvβ8 serves as a Novel Marker of Poor Prognosis in Colon Carcinoma and Regulates Cell Invasiveness through the Activation of TGF-β1

Zhou, Mingliang; Ni, Jun; Wang, Jinshen; Gao, Huijie; Shahbaz, Muhammad; Niu, Zhihong; Li, Zequn; Zou, Xueqing; Liang, Benjia

doi:10.7150/jca.43826

Cited by 13 publications

(6 citation statements)

References 45 publications

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“…72 Integrin αvβ8 is a receptor for TGF-β, which activates TGF-β signal transduction by binding with TGF-β. 73 Integrin αvβ8mediated TGF-β activation is involved in regulating neurovascular development, immune cell recruitment and activation, and stem cell migration or differentiation (such as neuroblast chain and neural stem cell migration, nonmyelinating Schwann cell, and mesenchymal stem cell differentiation). 74 Integrin α5β1 binds with numerous ligands, such as fibronectin, fibrinogen, fibrillin, osteopontin, and thrombospondin.…”

Section: Structure and Function Of The Integrin Familymentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

155

111

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Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

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Section: Structure and Function Of The Integrin Familymentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

155

111

View full text Add to dashboard Cite

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“…For example, integrin V6 can be expressed by CRC cells, which can then inactivate TGFβ by integrin αvβ6 subsequently activating fibroblasts that promote tumor invasion [ 86 ]. CRC integrin αvβ8 expressed on tumor cells is reported as a crucial regulatory function during cell adhesion in the tumor microenvironment and supports the activation of TGF-β1 [ 87 ]. Several of these integrins, including integrin subunits β1, α6, β3, and β4, concentrated in healthy adult stem and progenitor cells, are also signs of CSCs.…”

Section: Participation Of Extracellular Matrix Components In Cancer P...mentioning

confidence: 99%

Cancer Stem Cells in Tumor Microenvironment of Adenocarcinoma of the Stomach, Colon, and Rectum

Islas

Quiroz-Reyes

Delgado-González

et al. 2022

Cancers

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Gastrointestinal adenocarcinomas are one of the world’s deadliest cancers. Cancer stem cells and the tissue microenvironment are highly regulated by cell and molecular mechanisms. Cancer stem cells are essential for maintenance and progression and are associated with resistance to conventional treatments. This article reviews the current knowledge of the role of the microenvironment during the primary establishment of gastrointestinal adenocarcinomas in the stomach, colon, and rectum and its relationship with cancer stem cells. We also describe novel developments in cancer therapeutics, such as targeted therapy, and discuss the advantages and disadvantages of different treatments for improving gastrointestinal cancer prognosis.

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“…This integrin is also overexpressed by several types of cancer cells, such as head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma (PDAC), breast, liver, colon, and ovarian cancers, and others 1 - 7 ; αvβ6 expression level is a prognostic indicator of poor survival in patients with various types of tumors 3 , 6 , 8 - 10 . The integrin αvβ8 is another cell-surface receptor expressed by astrocytes, dendritic cells, mural mesangial cells, and by various carcinoma cells and tumor infiltrating regulatory T cells 11 - 13 ; enhanced αvβ8 expression mediates radio/chemo-resistance in pancreatic cancer 13 and serves as a marker of poor prognosis in colon carcinoma patients 14 .…”

Section: Introductionmentioning

confidence: 99%

A stapled chromogranin A-derived peptide homes in on tumors that express αvβ6 or αvβ8 integrins

Monieri¹,

Rainone²,

Sacchi³

et al. 2023

Int. J. Biol. Sci.

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Rationale:The αvβ6and αvβ8-integrins, two cell-adhesion receptors upregulated in many tumors and involved in the activation of the latency associated peptide (LAP)/TGFβ complex, represent potential targets for tumor imaging and therapy. We investigated the tumor-homing properties of a chromogranin A-derived peptide containing an RGDL motif followed by a chemically stapled alpha-helix (called "5a"), which selectively recognizes the LAP/TGFβ complex-binding site of αvβ6 and αvβ8. Methods: Peptide 5a was labeled with IRDye 800CW (a near-infrared fluorescent dye) or with 18 F-NOTA (a label for positron emission tomography (PET)); the integrin-binding properties of free peptide and conjugates were then investigated using purified αvβ6/αvβ8 integrins and various αvβ6/αvβ8 single -or double-positive cancer cells; tumor-homing, biodistribution and imaging properties of the conjugates were investigated in subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, and in mice bearing subcutaneous αvβ8-positive prostate tumors. Results:In vitro studies showed that 5a can bind both integrins with high affinity and inhibits cell-mediated TGFβ activation. The 5a-IRDye and 5a-NOTA conjugates could bind purified αvβ6/αvβ8 integrins with no loss of affinity compared to free peptide, and selectively recognized various αvβ6/αvβ8 single-or double-positive cancer cells, including cells from pancreatic carcinoma, melanoma, oral mucosa, bladder and prostate cancer. In vivo static and dynamic optical near-infrared and PET/CT imaging and biodistribution studies, performed in mice with subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, showed high target-specific uptake of fluorescence-and radio-labeled peptide by tumors and low non-specific uptake in other organs and tissues, except for excretory organs. Significant target-specific uptake of fluorescence-labeled peptide was also observed in mice bearing αvβ8-positive prostate tumors. Conclusions:The results indicate that 5a can home to αvβ6and/or αvβ8-positive tumors, suggesting that this peptide can be exploited as a ligand for delivering imaging or anticancer agents to αvβ6/αvβ8 single-or double-positive tumors, or as a tumor-homing inhibitor of these TGFβ activators.

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Integrin αvβ8 serves as a Novel Marker of Poor Prognosis in Colon Carcinoma and Regulates Cell Invasiveness through the Activation of TGF-β1

Cited by 13 publications

References 45 publications

Targeting integrin pathways: mechanisms and advances in therapy

Targeting integrin pathways: mechanisms and advances in therapy

Cancer Stem Cells in Tumor Microenvironment of Adenocarcinoma of the Stomach, Colon, and Rectum

A stapled chromogranin A-derived peptide homes in on tumors that express αvβ6 or αvβ8 integrins

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