Integrin α5β1 in pancreatic ductal adenocarcinoma: Tumour‒stroma crosstalk, hypoxia and therapeutic targeting

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is characterised by aggressive biological behaviour, marked therapeutic resistance and a dense desmoplastic tumour microenvironment. Integrin α5β1, the principal fibronectin receptor, has emerged as an important mediator of tumour-stroma interactions through its roles in cell adhesion, mechanotransduction, migration, survival and extracellular matrix (ECM) remodelling.

Main body: Increasing evidence indicates that integrin alpha 5 (ITGA5)/integrin α5β1 is upregulated in PDAC cells and stromal compartments and is associated with invasion, fibrosis, therapeutic resistance and poor prognosis. Hypoxia, a defining feature of PDAC, may further enhance α5β1-related signalling by promoting stromal activation and ECM remodelling. This review summarises the structural and signalling features of integrin α5β1, its role in hypoxia-related interactions between tumour cells and the stroma, its contribution to therapeutic resistance in PDAC, and current therapeutic strategies targeting this integrin.

Conclusion: Integrin α5β1 is a biologically relevant therapeutic target for modulating the fibrotic stroma and overcoming treatment resistance in PDAC, and it may also be implicated in tumorstroma crosstalk within the hypoxic microenvironment. Successful clinical translation of α5β1-targeted strategies will likely require further mechanistic investigation, biomarker-guided patient selection, and rational combination approaches to address pathway redundancy and the limited efficacy of monotherapy.

Keywords

hypoxia / integrin α5β1 / pancreatic ductal adenocarcinoma / volociximab

References

[1] Filho AM, Laversanne M, Ferlay J, et al. The GLOBOCAN 2022 cancer estimates: data sources, methods, and a snapshot of the cancer burden worldwide. Int J Cancer. 2025; 156(7): 1336-1346.

[2] Zhang T, Jiang H, Xu X, Zhao Z, Zhou M. Non-communicable disease burden in China, 1990‒2023: evidence from the Global Burden of Disease Study 2023. Chin Med J (Engl). 2026; 139(1): 48-57.

[3] Yu B, Shao S, Ma W. Frontiers in pancreatic cancer on biomarkers, microenvironment, and immunotherapy. Cancer Lett. 2025; 610:217350.

[4] Sahai E, Astsaturov I, Cukierman E, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020; 20(3): 174-186.

[5] Shah VM, Sheppard BC, Sears RC, Alani AW. Hypoxia: friend or foe for drug delivery in pancreatic cancer. Cancer Lett. 2020; 492: 63-70.

[6] Jin X, Dai L, Ma Y, Wang J, Liu Z. Implications of HIF-1alpha in the tumorigenesis and progression of pancreatic cancer. Cancer Cell Int. 2020; 20: 273.

[7] Wang J, Shen J, Zhao K, Hu J, Dong J, Sun J. STIM1 overexpression in hypoxia microenvironment contributes to pancreatic carcinoma progression. Cancer Biol Med. 2019; 16(1): 100-108.

[8] Zhu H, Wang G, Zhu H, Xu A. ITGA5 is a prognostic biomarker and correlated with immune infiltration in gastrointestinal tumors. BMC Cancer. 2021; 21(1): 269.

[9] Sun Z, Guo SS, Fässler R. Integrin-mediated mechanotransduction. J Cell Biol. 2016; 215(4): 445-456.

[10] Hou J, Yan D, Liu Y, Huang P, Cui H. The roles of integrin alpha5beta1 in human cancer. Onco Targets Ther. 2020; 13: 13329-13344.

[11] Saraswathibhatla A, Indana D, Chaudhuri O. Cell‒extracellular matrix mechanotransduction in 3D. Nat Rev Mol Cell Biol. 2023; 24(7): 495-516.

[12] Xiao Y, Li Y, Tao H, et al. Integrin α5 down-regulation by miR-205 suppresses triple negative breast cancer stemness and metastasis by inhibiting the Src/Vav2/Rac1 pathway. Cancer Lett 2018; 433: 199-209.

[13] Li D, Sun A, Zhang L, et al. Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2. Theranostics. 2022; 12(17): 7431-7449.

[14] Zhou L, Liu Y, Zhang Y, Hu F, Shen L, Hou S. ITGA5 promotes cervical cancer progression by regulating IMP3 recruitment of HK2 mRNA. Am J Transl Res. 2025; 17(4): 3031-3049.

[15] Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002; 110(6): 673-87.

[16] Takada Y, Ye X, Simon S. The integrins. Genome Biol. 2007; 8(5):215.

[17] Hamidi H, Ivaska J. Every step of the way: integrins in cancer progression and metastasis. Nat Rev Cancer. 2018; 18(9): 533-548.

[18] Nagae M, Re S, Mihara E, Nogi T, Sugita Y, Takagi J. Crystal structure of α5β1 integrin ectodomain: atomic details of the fibronectin receptor. J Cell Biol. 2012; 197(1): 131-40.

[19] Huang R, Rofstad EK. Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma. J Exp Clin Cancer Res. 2018; 37(1): 92.

[20] Sun L, Guo S, Xie Y, Yao Y. The characteristics and the multiple functions of integrin beta1 in human cancers. J Transl Med. 2023; 21(1): 787.

[21] Li S, Sampson C, Liu C, Piao HL, Liu HX. Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities. Cell Commun Signal. 2023; 21(1): 266.

[22] Liu F, Wu Q, Dong Z, Liu K. Integrins in cancer: emerging mechanisms and therapeutic opportunities. Pharmacol Ther. 2023; 247:108458.

[23] Delon I, Brown NH. Integrins and the actin cytoskeleton. Curr Opin Cell Biol. 2007; 19(1): 43-50.

[24] Sun CC, Qu XJ, Gao ZH. Arginine‒glycine‒aspartate-binding integrins as therapeutic and diagnostic targets. Am J Ther. 2016; 23(1): e198-207.

[25] Zollinger AJ, Smith ML. Fibronectin, the extracellular glue. Matrix Biol. 2017; 60-61: 27-37.

[26] Kuramoto K, Liang H, Hong JH, He C. Exercise-activated hepatic autophagy via the FN1‒α5β1 integrin pathway drives metabolic benefits of exercise. Cell Metab. 2023; 35(4): 620-632.e5.

[27] Fujita M, Sasada M, Iyoda T, Fukai F. Involvement of integrin-activating peptides derived from tenascin-C in cancer aggression and new anticancer strategy using the fibronectin-derived integrin-inactivating peptide. Molecules. 2020; 25(14):3239.

[28] Stefanelli VL, Choudhury S, Hu P, et al. Citrullination of fibronectin alters integrin clustering and focal adhesion stability promoting stromal cell invasion. Matrix Biol. 2019; 82: 86-104.

[29] Uetaki M, Onishi N, Oki Y, et al. Regulatory roles of fibronectin and integrin α5 in reorganization of the actin cytoskeleton and completion of adipogenesis. Mol Biol Cell. 2022; 33(9): ar78.

[30] Pankov R, Cukierman E, Katz BZ, et al. Integrin dynamics and matrix assembly: tensin-dependent translocation of alpha(5)beta(1) integrins promotes early fibronectin fibrillogenesis. J Cell Biol. 2000; 148(5): 1075-1090.

[31] Chen M, Cavinato C, Hansen J, et al. FN (fibronectin)‒integrin α5 signaling promotes thoracic aortic aneurysm in a mouse model of Marfan syndrome. Arterioscler Thromb Vasc Biol. 2023; 43(5): e132-e150.

[32] Leppänen J, Lindholm V, Isohookana J, et al. Tenascin C, fibronectin, and tumor‒stroma ratio in pancreatic ductal adenocarcinoma. Pancreas. 2019; 48(1): 43-48.

[33] Sigirli S, Karakas D. Fibrotic fortresses and therapeutic frontiers: pancreatic stellate cells and the extracellular matrix in pancreatic cancer. Cancer Med. 2025; 14(11):e70788.

[34] Sil H, Sen T, Chatterjee A. Fibronectin-integrin (alpha5beta1) modulates migration and invasion of murine melanoma cell line B16F10 by involving MMP-9. Oncol Res. 2011; 19(7): 335-48.

[35] Peng Z, Hao M, Tong H, et al. The interactions between integrin α(5)β(1) of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis. Int J Biol Sci. 2022; 18(13): 5019-5037.

[36] Orecchia A, Lacal PM, Schietroma C, Morea V, Zambruno G, Failla CM. Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for the alpha 5 beta 1 integrin. J Cell Sci. 2003; 116(pt 17): 3479-3489.

[37] Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010; 10(1): 9-22.

[38] Wei Y, Czekay RP, Robillard L, et al. Regulation of alpha5beta1 integrin conformation and function by urokinase receptor binding. J Cell Biol. 2005; 168(3): 501-11.

[39] Bachsais M, Naddaf N, Yacoub D, et al. The interaction of CD154 with the α5β1 integrin inhibits Fas-induced T cell death. PLoS One. 2016; 11(7):e0158987.

[40] Wang T, Ward Y, Tian L, et al. CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells. Blood. 2005; 105(7): 2836-2844.

[41] Cao Y, Hoeppner LH, Bach S, et al. Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin. Cancer Res. 2013; 73(14): 4579-4590.

[42] Shen M, Jiang YZ, Wei Y, et al. Tinagl1 suppresses triple-negative breast cancer progression and metastasis by simultaneously inhibiting integrin/FAK and EGFR signaling. Cancer Cell. 2019; 35(1): 64-80.e7.

[43] Rattila S, Dunk CEE, Im M, et al. Interaction of pregnancy-specific glycoprotein 1 with integrin α5β1 is a modulator of extravillous trophoblast functions. Cells. 2019; 8(11):1369.

[44] Lv X, Li Z, Guan J, et al. Porcine hemagglutinating encephalomyelitis virus activation of the integrin α5β1-FAK-cofilin pathway causes cytoskeletal rearrangement to promote its invasion of N2a cells. J Virol. 2019; 93(5):e01736-18.

[45] Pokharel SM, Shil NK, Gc JB, et al. Integrin activation by the lipid molecule 25-hydroxycholesterol induces a proinflammatory response. Nat Commun. 2019; 10(1): 1482.

[46] Takagi J, Petre BM, Walz T, Springer TA. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell. 2002; 110(5): 599-611.

[47] Hang Q, Isaji T, Hou S, Zhou Y, Fukuda T, Gu J. N-glycosylation of integrin α5 acts as a switch for EGFR-mediated complex formation of integrin α5β1 to α6β4. Sci Rep. 2016; 6:33507.

[48] Molnár M, Sőth Á, Simon-Vecsei Z. Pathways of integrins in the endo-lysosomal system. Biol Futur. 2022; 73(2): 171-185.

[49] Mythreye K, Knelson EH, Gatza CE, Gatza ML, Blobe GC. TβRIII/β-arrestin2 regulates integrin α5β1 trafficking, function, and localization in epithelial cells. Oncogene. 2013; 32(11): 1416-1427.

[50] Chen W, Harbeck MC, Zhang W, Jacobson JR. MicroRNA regulation of integrins. Transl Res. 2013; 162(3): 133-143.

[51] Kuninty PR, Bansal R, De Geus SWL, et al. ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer. Sci Adv. 2019; 5(9):eaax2770.

[52] Yao H, Zeng ZZ, Fay KS, et al. Role of α(5)β(1) integrin up-regulation in radiation-induced invasion by human pancreatic cancer cells. Transl Oncol. 2011; 4(5): 282-292.

[53] Haider S, Wang J, Nagano A, et al. A multi-gene signature predicts outcome in patients with pancreatic ductal adenocarcinoma. Genome Med. 2014; 6(12): 105.

[54] Wang T, Yang J, Mao J, et al. ITGA5 inhibition in pancreatic stellate cells re-educates the in vitro tumor‒stromal crosstalk. Med Oncol. 2022; 40(1): 39.

[55] Lowrie AG, Salter DM, Ross JA. Latent effects of fibronectin, alpha5beta1 integrin, alphaVbeta5 integrin and the cytoskeleton regulate pancreatic carcinoma cell IL-8 secretion. Br J Cancer. 2004; 91(7): 1327-1334.

[56] Wu G, Wang D, Xiong F, et al. The emerging roles of CEACAM6 in human cancer (review). Int J Oncol. 2024; 64(3): 27.

[57] Duxbury MS, Matros E, Clancy T, et al. CEACAM6 is a novel biomarker in pancreatic adenocarcinoma and PanIN lesions. Ann Surg. 2005; 241(3): 491-496.

[58] Kurlinkus B, Ger M, Kaupinis A, Jasiunas E, Valius M, Sileikis A. CEACAM6's role as a chemoresistance and prognostic biomarker for pancreatic cancer: a comparison of CEACAM6's diagnostic and prognostic capabilities with those of CA19-9 and CEA. Life (Basel). 2021; 11(6):542.

[59] Duxbury MS, Ito H, Benoit E, Ashley SW, Whang EE. CEACAM6 is a determinant of pancreatic adenocarcinoma cellular invasiveness. Br J Cancer. 2004; 91(7): 1384-1390.

[60] Chen J, Li Q, An Y, et al. CEACAM6 induces epithelial‒mesenchymal transition and mediates invasion and metastasis in pancreatic cancer. Int J Oncol. 2013; 43(3): 877-885.

[61] Pandey R, Zhou M, Islam S, et al. Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in pancreatic ductal adenocarcinoma (PDA): an integrative analysis of a novel therapeutic target. Sci Rep. 2019; 9(1):18347.

[62] Ordonez C, Zhai AB, Camacho-Leal P, Demarte L, Fan MM, Stanners CP. GPI-anchored CEA family glycoproteins CEA and CEACAM6 mediate their biological effects through enhanced integrin alpha5beta1-fibronectin interaction. J Cell Physiol. 2007; 210(3): 757-765.

[63] Al-Khinji A. Exploring the interactions of integrins and CEACAM6 (review). Exp Ther Med. 2025; 30(6): 237.

[64] Duxbury MS, Ito H, Ashley SW, Whang EE. c-Src-dependent cross-talk between CEACAM6 and alphavbeta3 integrin enhances pancreatic adenocarcinoma cell adhesion to extracellular matrix components. Biochem Biophys Res Commun. 2004; 317(1): 133-141.

[65] Arao S, Masumoto A, Otsuki M. Beta1 integrins play an essential role in adhesion and invasion of pancreatic carcinoma cells. Pancreas. 2000; 20(2): 129-137.

[66] Li NF, Gemenetzidis E, Marshall FJ, et al. RhoC interacts with integrin α5β1 and enhances its trafficking in migrating pancreatic carcinoma cells. PLoS One. 2013; 8(12):e81575.

[67] Kim S, Bell K, Mousa SA, Varner JA. Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol. 2000; 156(4): 1345-1362.

[68] Kim S, Bakre M, Yin H, Varner JA. Inhibition of endothelial cell survival and angiogenesis by protein kinase A. J Clin Invest. 2002; 110(7): 933-941.

[69] Zhang C, Zhou T, Chen Z, et al. Coupling of integrin α5 to annexin A2 by flow drives endothelial activation. Circ Res. 2020; 127(8): 1074-1090.

[70] Erkan M, Reiser-Erkan C, Michalski CW, et al. Cancer‒stellate cell interactions perpetuate the hypoxia‒fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia. 2009; 11(5): 497-508.

[71] Matsuo Y, Ding Q, Desaki R, et al. Hypoxia inducible factor-1 alpha plays a pivotal role in hepatic metastasis of pancreatic cancer: an immunohistochemical study. J Hepatobiliary Pancreat Sci. 2014; 21(2): 105-112.

[72] Poh AR, Ernst M. Functional roles of SRC signaling in pancreatic cancer: recent insights provide novel therapeutic opportunities. Oncogene. 2023; 42(22): 1786-1801.

[73] Miao MZ, Lee JS, Yamada KM, Loeser RF. Integrin signalling in joint development, homeostasis and osteoarthritis. Nat Rev Rheumatol. 2024; 20(8): 492-509.

[74] Parkin A, Man J, Timpson P, Pajic M. Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy. FEBS J. 2019; 286(18): 3510-3539.

[75] Li J, Peng L, Chen Q, et al. Integrin β1 in pancreatic cancer: expressions, functions, and clinical implications. Cancers (Basel). 2022; 14(14):3377.

[76] Dawson JC, Serrels A, Stupack DG, Schlaepfer DD, Frame MC. Targeting FAK in anticancer combination therapies. Nat Rev Cancer. 2021; 21(5): 313-324.

[77] Cucchiara M, Palano MT, Rubuano C, et al. The TGF-βR1 inhibitor galunisertib re-shapes the PDAC-TME by limiting decidual-like natural killer cells polarization. Cell Death Dis. 2026: 577.

[78] Li R, Wei F, Yang M. TGF-beta in hematologic malignancies: molecular functions and clinical applications. Front Immunol. 2026; 17:1728730.

[79] Tian H, Mythreye K, Golzio C, Katsanis N, Blobe GC. Endoglin mediates fibronectin/α5β1 integrin and TGF-β pathway crosstalk in endothelial cells. EMBO J. 2012; 31(19): 3885-3900.

[80] Grzesiak JJ, Smith KC, Burton DW, Deftos LJ, Bouvet M. GSK3 and PKB/Akt are associated with integrin-mediated regulation of PTHrP, IL-6 and IL-8 expression in FG pancreatic cancer cells. Int J Cancer. 2005; 114(4): 522-530.

[81] Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023; 22(1): 138.

[82] Chen B, Li J, Fellows GF, Sun Z, Wang R. Maintaining human fetal pancreatic stellate cell function and proliferation require β1 integrin and collagen I matrix interactions. Oncotarget. 2015; 6(16): 14045-14059.

[83] Wang JF, Chen YY, Zhang SW, et al. ITGA5 promotes tumor progression through the activation of the FAK/AKT signaling pathway in human gastric cancer. Oxid Med Cell Longev. 2022; 2022:8611306.

[84] Luo J, Jiang Y, Wu L, et al. Long non-coding RNA ABHD11-AS1 promotes colorectal cancer progression and invasion through targeting the integrin subunit alpha 5/focal adhesion kinase/phosphoinositide 3 kinase/Akt signaling pathway. Aging (Albany NY). 2021; 13(16): 20179-20191.

[85] Zhang M, Li J, Meng X, et al. ITGA5 induces mesenchymal transformation to promote gliomas progression via PI3K/AKT/mTORC1 signaling pathway. Sci Rep. 2025; 15(1):13539.

[86] Yang Y, Wang Y, Che X, et al. Integrin α5 promotes migration and invasion through the FAK/STAT3/AKT signaling pathway in icotinib-resistant non-small cell lung cancer cells. Oncol Lett. 2021; 22(1): 556.

[87] Rubio K, Romero-Olmedo AJ, Sarvari P, et al. Non-canonical integrin signaling activates EGFR and RAS‒MAPK‒ERK signaling in small cell lung cancer. Theranostics. 2023; 13(8): 2384-2407.

[88] Topalovski M, Brekken RA. Matrix control of pancreatic cancer: new insights into fibronectin signaling. Cancer Lett. 2016; 381(1): 252-258.

[89] Mao H, Zhao X, Sun SC. NF-κB in inflammation and cancer. Cell Mol Immunol. 2025; 22(8): 811-839.

[90] Han SW, Roman J. Fibronectin induces cell proliferation and inhibits apoptosis in human bronchial epithelial cells: pro-oncogenic effects mediated by PI3-kinase and NF-kappa B. Oncogene. 2006; 25(31): 4341-4349.

[91] Dia VP, de Mejia EG. Lunasin potentiates the effect of oxaliplatin preventing outgrowth of colon cancer metastasis, binds to α5β1 integrin and suppresses FAK/ERK/NF-κB signaling. Cancer Lett. 2011; 313(2): 167-180.

[92] Guo M, Sahni SK, Sahni A, Francis CW. Fibrinogen regulates the expression of inflammatory chemokines through NF-kappaB activation of endothelial cells. Thromb Haemost. 2004; 92(4): 858-866.

[93] Ghosh C, Kakar R, Torkamboor S, Sun Y. The regulation and function of Hippo/YAP pathway in cancer. FASEB J. 2026; 40(7):e71744.

[94] Li B, He J, Lv H, et al. c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow. J Clin Invest. 2019; 129(3): 1167-1179.

[95] He S, Huang Q, Hu J, et al. EWS-FLI1-mediated tenascin-C expression promotes tumour progression by targeting MALAT1 through integrin α5β1-mediated YAP activation in Ewing sarcoma. Br J Cancer. 2019; 121(11): 922-933.

[96] Mamidi A, Prawiro C, Seymour PA, et al. Mechanosignalling via integrins directs fate decisions of pancreatic progenitors. Nature. 2018; 564(7734): 114-118.

[97] Zhang Z, Qiu N, Yin J, et al. SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression. Theranostics. 2020; 10(10): 4290-4307.

[98] Ding L, Chen W, Luo C, et al. Triptolide targets PPP2CA/ITGA5 axis to suppress lactate-driven ovarian cancer progression. Chin Med. 2025; 20(1): 122.

[99] Shi Y, Gilkes DM. HIF-1 and HIF-2 in cancer: structure, regulation, and therapeutic prospects. Cell Mol Life Sci. 2025; 82(1): 44.

[100] Tao J, Yang G, Zhou W, et al. Targeting hypoxic tumor microenvironment in pancreatic cancer. J Hematol Oncol. 2021; 14(1): 14.

[101] Wicks EE, Semenza GL. Hypoxia-inducible factors: cancer progression and clinical translation. J Clin Invest. 2022; 132(11):e159839.

[102] Ju JA, Godet I, Ye IC, et al. Hypoxia selectively enhances integrin alpha(5)beta(1) receptor expression in breast cancer to promote metastasis. Mol Cancer Res. 2017; 15(6): 723-734.

[103] Ryu MH, Park HM, Chung J, Lee CH, Park HR. Hypoxia-inducible factor-1alpha mediates oral squamous cell carcinoma invasion via upregulation of alpha5 integrin and fibronectin. Biochem Biophys Res Commun. 2010; 393(1): 11-15.

[104] Zhao X, Mai Z, Liu L, Lu Y, Cui L, Yu J. Hypoxia-driven TNS4 fosters HNSCC tumorigenesis by stabilizing integrin α5β1 complex and triggering FAK-mediated Akt and TGFβ signaling pathways. Int J Biol Sci. 2024; 20(1): 231-248.

[105] Cooper J, Giancotti FG. Integrin signaling in cancer: mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell. 2019; 35(3): 347-367.

[106] Pang X, He X, Qiu Z, et al. Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduct Target Ther. 2023; 8(1): 1.

[107] Lin L, Yan F, Zhao D, et al. Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3. Oncotarget. 2016; 7(9): 9844-9858.

[108] Hu Z, Gao S, Gao J, et al. Elevated levels of Lewis y and integrin α5β1 correlate with chemotherapeutic drug resistance in epithelial ovarian carcinoma. Int J Mol Sci. 2012; 13(12): 15588-15600.

[109] Damiano JS, Hazlehurst LA, Dalton WS. Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation. Leukemia. 2001; 15(8): 1232-1239.

[110] Martinkova E, Maglott A, Leger DY, et al. alpha5beta1 integrin antagonists reduce chemotherapy-induced premature senescence and facilitate apoptosis in human glioblastoma cells. Int J Cancer. 2010; 127(5): 1240-1248.

[111] Morozevich GE, Kozlova NI, Susova OY, Lupatov AY, Berman AE. Hyperexpression of integrin α5β1 promotes resistance of MCF-7 human breast carcinoma cells to doxorubicin via ERK protein kinase down-regulation. Biochemistry (Mosc). 2017; 82(9): 1017-1024.

[112] Almokadem S, Belani CP. Volociximab in cancer. Expert Opin Biol Ther. 2012; 12(2): 251-257.

[113] Schaffner F, Ray AM, Dontenwill M. Integrin α5β1, the fibronectin receptor, as a pertinent therapeutic target in solid tumors. Cancers (Basel). 2013; 5(1): 27-47.

[114] Ramakrishnan V, Bhaskar V, Law DA, et al. Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent. J Exp Ther Oncol. 2006; 5(4): 273-286.

[115] Bhaskar V, Zhang D, Fox M, et al. A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med. 2007; 5:61.

[116] Pantano F, Croset M, Driouch K, et al. Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions. Oncogene. 2021; 40(7): 1284-1299.

[117] Ricart AD, Tolcher AW, Liu G, et al. Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: a phase I, pharmacokinetic, and biological correlative study. Clin Cancer Res 2008; 14(23): 7924-7929.

[118] Evans T, Ramanathan RK, Yazji S, et al. Final results from cohort 1 of a phase II study of volociximab, an anti-α5β1 integrin antibody, in combination with gemcitabine (GEM) in patients (pts) with metastatic pancreatic cancer (MPC). J Clin Oncol. 2007; 25(18_suppl): 4549-4549.

[119] Bell-McGuinn KM, Matthews CM, Ho SN, et al. A phase II, single-arm study of the anti-α5β1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer. Gynecol Oncol. 2011; 121(2): 273-279.

[120] Besse B, Tsao LC, Chao DT, et al. Phase Ib safety and pharmacokinetic study of volociximab, an anti-α5β1 integrin antibody, in combination with carboplatin and paclitaxel in advanced non-small-cell lung cancer. Ann Oncol. 2013; 24(1): 90-96.

[121] Li G, Zhang L, Chen E, et al. Dual functional monoclonal antibody PF-04605412 targets integrin alpha5beta1 and elicits potent antibody-dependent cellular cytotoxicity. Cancer Res. 2010; 70(24): 10243-10254.

[122] Mateo J, Berlin J, de Bono JS, et al. A first-in-human study of the anti-α5β1 integrin monoclonal antibody PF-04605412 administered intravenously to patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014; 74(5): 1039-1046.

[123] Wang W, Wang F, Lu F, et al. The antiangiogenic effects of integrin alpha5beta1 inhibitor (ATN-161) in vitro and in vivo. Invest Ophthalmol Vis Sci. 2011; 52(10): 7213-7220.

[124] Gao RR, Ma LY, Chen JW, et al. ATN-161 alleviates caerulein-induced pancreatitis. J Genet Genomics. 2024; 51(12): 1447-1458.

[125] Khalili P, Arakelian A, Chen G, et al. A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo. Mol Cancer Ther. 2006; 5(9): 2271-2280.

[126] Stoeltzing O, Liu W, Reinmuth N, et al. Inhibition of integrin alpha5beta1 function with a small peptide (ATN-161) plus continuous 5-FU infusion reduces colorectal liver metastases and improves survival in mice. Int J Cancer. 2003; 104(4): 496-503.

[127] Cianfrocca ME, Kimmel KA, Gallo J, et al. Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH(2)), a beta integrin antagonist, in patients with solid tumours. Br J Cancer. 2006; 94(11): 1621-1626.

[128] Mardhian DF, Pednekar KP, Hemdan AG, et al. Engineered cyclic peptide targeting ITGA5 disrupts tumor-stroma interaction to overcome desmoplasia and resistance in pancreatic ductal adenocarcinoma. Acta Pharm Sin B. 2026; 16(1): 305-321.

[129] Maglott A, Bartik P, Cosgun S, et al. The small alpha5beta1 integrin antagonist, SJ749, reduces proliferation and clonogenicity of human astrocytoma cells. Cancer Res. 2006; 66(12): 6002-6007.

[130] Maier AK, Kociok N, Zahn G, et al. Modulation of hypoxia-induced neovascularization by JSM6427, an integrin alpha5beta1 inhibiting molecule. Curr Eye Res. 2007; 32(9): 801-812.

[131] Färber K, Synowitz M, Zahn G, et al. An alpha5beta1 integrin inhibitor attenuates glioma growth. Mol Cell Neurosci. 2008; 39(4): 579-585.

[132] Joshi R, Ren W, Mathew P. A bispecific antibody targeting the αv and α5β1 integrins induces integrin degradation in prostate cancer cells and is superior to monospecific antibodies. Mol Cancer Res. 2020; 18(1): 27-32.

[133] Joshi R, Zhou M, Lin JH, et al. A novel bispecific integrin α5β1/αv antibody reprograms the Myc-regulated basal phenotype of prostate cancer with NK cell-mediated tumor elimination. Mol Cancer Res. 2025; 23(10): 873-888.

[134] Bosnjak M, Dolinsek T, Cemazar M, et al. Gene electrotransfer of plasmid AMEP, an integrin-targeted therapy, has antitumor and antiangiogenic action in murine B16 melanoma. Gene Ther. 2015; 22(7): 578-590.

[135] Spanggaard I, Dahlstroem K, Laessoee L, et al. Gene therapy for patients with advanced solid tumors: a phase I study using gene electrotransfer to muscle with the integrin inhibitor plasmid AMEP. Acta Oncol. 2017; 56(7): 909-916.

[136] Slack RJ, Macdonald SJF, Roper JA, Jenkins RG, Hatley RJD. Emerging therapeutic opportunities for integrin inhibitors. Nat Rev Drug Discov. 2022; 21(1): 60-78.

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