doi: 10.4252/wjsc.v11.i8.476, 145. Nature (2019) 569:222–8. Bao ZZ, Lakonishok M, Kaufman S, Horwitz AF. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. GMI-1271 (Uproleselan), an E-selectin antagonist, is intended to inhibit E-selectin expression on endothelial cells so that E-selectin-mediated drug resistance in leukemia can be prevented. doi: 10.1023/A:1012445316415, 77. Cancers (Basel) (2019) 11. doi: 10.3390/cancers11091253, 134. B) allow for attachments between cells or between a cell and the extracellular matrix. J Cell Sci (2015) 128:1455–64. Yokosaki Y, Matsuura N, Sasaki T, Murakami I, Schneider H, Higashiyama S, et al. In T cell leukemias with gastrointestinal involvement, it was found that the expression of α4β7 is linked with homing to MAdCAM-1 on endothelial cells in the intestinal mucosa (235). Out of the three populations, the PD leukemic population planted under the BMSC layer demonstrated increased quiescence; resistance to cytarabine (Ara-C), methotrexate (MTX), and vincristine (VCR); and increased glycolysis (48). Celecoxib inhibits proliferation and survival of chronic myelogeous leukemia (CML) cells via AMPK-dependent regulation of beta-catenin and mTORC1/2. Therefore, disrupting the interactions between leukemia cells and the surrounding cells or ECM protein may lead to apoptosis or sensitization toward chemotherapy. This figure does not represent a comprehensive list of integrin heterodimers but rather includes integrins described by currently available publications in the field of leukemia, which are reviewed in this review. The efficacy of CAR T cells against αvβ3 in melanoma and αvβ6 in ovarian, breast, and pancreatic xenograft mice models has also been evaluated (238, 239) for integrin targeting CAR T therapy in hematological malignancies. Furthermore, ITGA3 knockdown with short hairpin RNA against ITGA3 did not affect the stemness of the cells but decreased the long-term reconstitution ability in NSG mice. doi: 10.1073/pnas.2009078117, 30. Cadherin inhibitors were developed based on compelling preclinical data and translated into clinical trials. Med Sci Monit (2018) 24:5860–73. Berrazouane et al. Horst E, Radaszkiewicz T, Hooftman-den Otter A, Pieters R, van Dongen JJ, Meijer CJ, et al. Figure 3 Dimerization of integrins in leukemia. One of the most well-known mechanisms of the BM–leukemia cell interaction is the CXCR4/CXCL12 axis (2, 49), yet there are many more surface molecules that are directly associated with adhesion and interaction (50–52). Cell adhesion molecules (CAMs) are cell surface proteins that are specialized for adhesion to other types of cells or the ECM. Hamidi H, Pietila M, Ivaska J. A large family of integral membrane proteins involved in signal transduction. doi: 10.4161/cam.18702, 59. Cells can also secret extracellular matrix (ECM) proteins that will bind to CAMs. 216. Have polarity, Makes up miccrotubles. Bistrian R, Dorn A, Mobest DC, Ruster B, Ludwig R, Scheele J, et al. Effects of CD49d-targeted antisense-oligonucleotide on alpha4 integrin expression and function of acute lymphoblastic leukemia cells: Results of in vitro and in vivo studies. Cancers (Basel) (2019) 11. doi: 10.3390/cancers11070978, 242. Celecoxib suppresses autophagy and enhances cytotoxicity of imatinib in imatinib-resistant chronic myeloid leukemia cells. Wright SD, Weitz JI, Huang AJ, Levin SM, Silverstein SC, Loike JD. Moreover, the downregulation of E-cadherin suppressed the adhesion of AML cells to BM-derived MSCs and enhanced the anti-leukemic effect of cytarabine (27). J Clin Oncol (2011) 29:1210–5. J Cell Biol (1987) 105:2501–10. Cell Death Dis (2016) 7:e2201. Blood (2018) 131:1507–11. Type of electrophoresis used to separate proteins based on charge. Borowitz MJ, Wood BL, Devidas M, Loh ML, Raetz EA, Salzer WL, et al. This is meant to simulate a gravitational pull. Nat Med (2017) 23:1436–43. 168. Kotha J, Longhurst C, Appling W, Jennings LK. Typically studies the H nucleus, but done with C-13 and others as well (only H on MCAT). Exp Cell Res (2017) 358:78–85. Galan-Diez M, Cuesta-Dominguez A, Kousteni S. The Bone Marrow Microenvironment in Health and Myeloid Malignancy. doi: 10.3324/haematol.11796, 170. Chromatographic procedure in which a mixture is placed on a stationary column filled with silica or alumina beads as an adsorbent, and gravity moves the solvent and compounds down the column. Ca2+ is required for stabilization of extracellular domain (54–56), as well as in selectins for proper binding to ligands (57). CAMs are divided into four major categories: cadherins, integrins, selectins and members of the immunoglobulin superfamily. Stoeltzing O, Liu W, Reinmuth N, Fan F, Parry GC, Parikh AA, et al. Neuro Oncol (2015) 17:708–17. Cadherins, selectins, and integrins are known cell adhesion molecules that are involved in CAM-DR in leukemia (Figure 5). The regulation of integrin function by divalent cations. J Immunol (1991) 146:4149–56. doi: 10.1007/s12307-010-0035-6, 99. Oncol Rep (2019) 42:521–32. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Support of acute lymphoblastic leukemia cells by nonmalignant bone marrow stromal cells. The fibrin-derived peptide Bbeta(15-42) significantly attenuates ischemia-reperfusion injury in a cardiac transplant model. COX-2 regulates E-cadherin expression through the NF-kappaB/Snail signaling pathway in gastric cancer. A transmembrane protein that interconnects the extracellular matrix and the cytoskeleton. Naci D, Berrazouane S, Barabé F, Aoudjit F. Cell adhesion to collagen promotes leukemia resistance to doxorubicin by reducing DNA damage through the inhibition of Rac1 activation. doi: 10.1038/nature06685, 37. Targeting of alpha(v)-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer. This method selectively and sequentially removes the N-terminal amino acid of the protein. As for other integrins, targeting the active form of the integrin β7 subunit, specifically the MMG49 epitope in the N-terminal region of active β7, showed multiple anti-myeloma effects in vivo without damaging normal hematopoietic cells (237). Yokosaki Y, Palmer EL, Prieto AL, Crossin KL, Bourdon MA, Pytela R, et al. Complement receptor type three (CD11b/CD18) of human polymorphonuclear leukocytes recognizes fibrinogen. Eur J Haematol (2020) 105:578–87. Calderwood DA, Campbell ID, Critchley DR. Talins and kindlins: partners in integrin-mediated adhesion. Leukemia (2007) 21:1189–97. The overexpression of VE-cadherin on Ph+/VE-cadherin+ LSC populations stabilizes β-catenin, maintaining β-catenin as constitutively active and thus promoting self-renewal independent of Wnt signaling. Selectins (CD62) are single-chain transmembrane glycoproteins that mediate calcium-dependent carbohydrate-binding. Methylation-independent ITGA2 overexpression is associated with poor prognosis in de novo acute myeloid leukemia. J Biol Chem (2018) 293:6869–82. doi: 10.1002/cncr.31848, 15. Miyake K, Medina K, Ishihara K, Kimoto M, Auerbach R, Kincade PW. Shah CA, Bei L, Wang H, Altman JK, Platanias LC, Eklund EA. J Cell Sci (2018) 131. doi: 10.1242/jcs.201707, 74. Joshi I, Yoshida T, Jena N, Qi X, Zhang J, Van Etten RA, et al. 194. PBM induced a stimulatory effect on various CAMs namely cadherins, integrins, selectins and immunoglobulins, and hence may be used as a complementary therapy in advancing treatment of non-healing diabetic ulcers. De Toni F, Racaud-Sultan C, Chicanne G, Mas VM, Cariven C, Mesange F, et al. doi: 10.1038/s41586-018-0342-5, 191. 246. Alpha 7 beta 1 integrin is a component of the myotendinous junction on skeletal muscle. Exp Hematol (2016) 44:363–77.e5. They allow epithelial molecules to attach to each other. doi: 10.1038/bjc.2016.312, 154. Wallstabe L, Mades A, Frenz S, Einsele H, Rader C, Hudecek M. CAR T cells targeting alphavbeta3 integrin are effective against advanced cancer in preclinical models. Kechagia JZ, Ivaska J, Roca-Cusachs P. Integrins as biomechanical sensors of the microenvironment. Wang L, O’Leary H, Fortney J, Gibson LF. Radice, G., Ferreira-Cornwell, M.C., Robinson, S.D., Rayburn, H., Chodosh, L.A., Takeichi, M. and Hynes, R.O. Anat Rec (Hoboken) (2016) 299:990–8. Borsig L. Selectins in cancer immunity. VLA-3 mediated adhesion to fibronectin requires RGD-motif recognition, whereas binding to collagen and laminin does not require an RGD-motif in the ligands (166). The interaction between leukemia cells and the bone microenvironment is known to provide drug resistance in leukemia cells. J Biol Chem (1993) 268:26773–83. Match. Mahlknecht U, Schonbein C. Histone deacetylase inhibitor treatment downregulates VLA-4 adhesion in hematopoietic stem cells and acute myeloid leukemia blast cells. Gut (2017) 66:839–51. This suggests a role of N-cadherin in maintaining the stem cell-like properties and survival of LSCs, which results in relapse. This adhesion is specifically mediated by ITGA6 and ITGB4 expression on EVI1 AML cells, and small-hairpin RNA against EVI1 decreased the expression of ITGA6 and ITGB4. Type of liquid chromatography, ions and polar molecules are separated based on characterisitic charge properties. Cardiovasc Res (2015) 107:331–9. GMI-1271 is currently the only selectin inhibitor in clinical trials and is being investigated for its safety and efficacy in AML patients (Table 3). A novel radiotracer 99mTc-RWY detecting integrin alpha 6 is in an early phase I clinical trial for SPECT imaging in breast cancer (NCT04289532), and the safety of the radiotracer and potential clinical applications are being evaluated. Alpha 4 beta 7 integrin mediates B cell binding to fibronectin and vascular cell adhesion molecule-1. This “cadherin switching” enables tumor cells to acquire a metastatic phenotype that is different from the parental population. 235. 10:592733. doi: 10.3389/fonc.2020.592733. Targeting of Aberrant alphavbeta6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells. Important in binding to and communicating with the ECM, role in cellular signaling and promotes cell division, apoptosis and other processes. Separating the components within the stationary phase based on the varying retention times of each compound. Hadzijusufovic E, Albrecht-Schgoer K, Huber K, Hoermann G, Grebien F, Eisenwort G, et al. Cancer (2009) 115:4766–74. Target Oncol (2019) 14:479–89. Cadherin mediated protein complex formation is observed at adherens junction where adjacent cells are connected to each other. Integrin trafficking at a glance. doi: 10.1038/s41556-019-0309-2, 130. Gang EJ, Kim HN, Hsieh YT, Ruan Y, Ogana H, Pham J, et al. /r/MCAT is a place for MCAT practice, questions, discussion, advice, social networking, news, study tips and more. Blood Cancer J (2019) 9:68. doi: 10.1038/s41408-019-0227-3, 139. Motor proteins that play key roles in aligning chromosomes during metaphase and depolymerizing microtubules during anaphase of mitosis. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Acad. doi: 10.1016/j.mayocp.2016.09.010, 14. Blood (2020) 136(2):210–23. Learn. Loading... Unsubscribe from CancerQuest-EmoryUniversity? Eur J Biochem (1994) 225:975–84. In fact, a high baseline level of soluble E-selectin along with VEGF, PAI-1, and low initial soluble ICAM-1 were proposed as prognostic factors for poor outcomes in pediatric ALL (135). Integrin-αV can dimerize with β1, β3, β5, β6, and β8. Moreover, the inhibition of ITGA6 or ITGB4 with neutralizing antibodies restored chemosensitivity against Ara-C in EVI+ AML cells. Zhang P, Zhang C, Li J, Han J, Liu X, Yang H. The physical microenvironment of hematopoietic stem cells and its emerging roles in engineering applications. An immune response in which the binding of antibodies to the surface of a microbe facilitates phagocytosis of the the microbe by a macrophage. Structure and functions of classical cadherins. Indeed, N-cadherin+ cell bearing mice had a significantly shorter survival than the N-cadherin− engrafted mice. Estrugo D, Fischer A, Hess F, Scherthan H, Belka C, Cordes N. Ligand bound beta1 integrins inhibit procaspase-8 for mediating cell adhesion-mediated drug and radiation resistance in human leukemia cells. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. Wang YP, Wang QY, Li CH, Li XW. doi: 10.1002/jcla.23151, 199. Publications about cadherins. J Cell Sci (1993) 106(Pt 2):579–89. Combretastatin decreased VCAM-1 and VE-cadherin on BMECs, and dislodged AML cells shifted G0/G1 to G2/M in their cell cycle. Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. The se-lectins and hyaluronate receptors mediate interactions between proteins and carbohy-drates. HK, YR, HO, and YK wrote, reviewed, and editing. Enhanced T-lineage acute lymphoblastic leukaemia cell survival on bone marrow stroma requires involvement of LFA-1 and ICAM-1. Because the endothelium binding of leukocytes is a prerequisite of metastasis, selectins are well-known to be involved in cancer progression (128, 129). At the same time, leukemia cells can aberrantly express CAM to facilitate surface molecule-mediated interaction with BM microenvironment, thereby inducing cell-adhesion mediated drug resistance (CAM-DR). doi: 10.1083/jcb.114.3.557. Nat Rev Cancer (2020) 20:158–73. They transfport or sequester molecules by binding to them. Urol Oncol (2015) 33:387 e17–27. For blood cancers, it has been suggested that the expression of α4β7 plays a role in the leukemic evolution of T cell lymphoblastic lymphomas and the dissemination of lymphoma cells to VCAM-1-positive vascular spaces (234). Figure 4 Integrin signaling in leukemia. Hematol Oncol Clin North Am (2009) 23:1083–98, vii. Cell (2005) 123:903–15. Celecoxib induces epithelial-mesenchymal transition in epithelial ovarian cancer cells via regulating ZEB1 expression. DiGiuseppe JA, Fuller SG, Borowitz MJ. Cell Stem Cell (2019) 24:769–84 e6. As discussed in this section, integrin blockades have been shown to increase chemosensitivity of leukemia cells and provide support for further studies of integrins as a viable target to abolish CAM-DR in leukemia. doi: 10.12659/MSM.907446, 250. Semin Immunol (2002) 14:73–81. doi: 10.1016/j.celrep.2019.06.084. The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. doi: 10.1111/j.1432-1033.1994.0975b.x, 157. Walter RB, Alonzo TA, Gerbing RB, Ho PA, Smith FO, Raimondi SC, et al. J Clin Lab Anal (2020) 34:e23151. Cold Spring Harb Perspect Med (2018) 8. doi: 10.1101/cshperspect.a031328, 62. BM includes many types of cellular and non-cellular components. Recently, the dual inhibition of α4β1 and α9β1 with BOP {[N-(benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl]tyrosine, a small molecule antagonist against integrin α4β1 and α9β1} demonstrated the successful HSC mobilization potential from the bone marrow to the peripheral blood. doi: 10.1080/10428194.2018.1434886, 146. Cadherin switching. VLA-5 has been suggested as a therapeutic target in leukemia. In an early study using T cells derived from leukocyte adhesion deficient (LAD) patients with genetic defects in β2 showed a decreased expression of LFA-1 and LFA-1 LAD derived T cells still bound to endothelial cells similar to normal T cells via complementary binding through VLA-4, but their transmigration through the endothelial layer of LAD derived T cells was significantly decreased (206). Indeed, the BM microenvironment is known to govern leukemia quiescence (2–4), proliferation (5), drug resistance (6), and leukemogenesis (7). doi: 10.1002/stem.1626, 68. Prognostic value of increased integrin-beta 1 expression in solid cancers: a meta-analysis. Muz B, Azab F, Fiala M, King J, Kohnen D, Fogler WE, et al. Integrin alpha1beta1 (VLA-1) mediates adhesion of activated intraepithelial lymphocytes to collagen. Blood (2000) 95:3208–13. Analysis utilizing CD18-deficient T cell clones. COX-2 inhibition by celecoxib in epithelial ovarian cancer attenuates E-cadherin suppression through reduced Snail nuclear translocation. Cadherins can be subdivided into several different groups including Type I and Type II classical cadherins (76), desmosomal cadherins (77), proto-cadherins (78), seven-pass transmembrane cadherins, and FAT and Dachsous cadherins (79). Houshmand M, Simonetti G, Circosta P, Gaidano V, Cignetti A, Martinelli G, et al. α1β1 is also called very late antigen 1 (VLA-1) because it is expressed on the surface of long-term activated T cells (158). doi: 10.1016/j.ymthe.2016.10.012, 240. doi: 10.18632/oncotarget.10189, 218. Glycobiology (2018) 28:648–55. Villatoro A, Konieczny J, Cuminetti V, Arranz L. Leukemia Stem Cell Release From the Stem Cell Niche to Treat Acute Myeloid Leukemia. 65. Stem Cell Res Ther (2019) 10:327. doi: 10.1186/s13287-019-1422-7, 70. Gruszka AM, Valli D, Restelli C, Alcalay M. Adhesion Deregulation in Acute Myeloid Leukaemia. Deschaseaux F, Charbord P. Human marrow stromal precursors are alpha 1 integrin subunit-positive. They allow epithelial molecules to attach to each other. Chen H, Hori T, Maeda M, Uchiyama T. Identification of an adhesion molecule expressed on adult T cell leukemia cells derived from a patient with gastrointestinal involvement: implication for a possible role of integrin beta 7 in leukemic cell infiltration into intestinal mucosa. doi: 10.1002/ijc.10958, 251. Chronic lymphocytic leukemia (CLL) treatment: So many choices, such great options. Chen Z, Liu M, Liu X, Huang S, Li L, Song B, et al. The extracellular domain of CAMs recognizes specific ligands or counter-receptors, and the intracellular (cytoplasmic) domain translates external stimuli into intracellular signalings, while the transmembrane domain stabilizes the structure of the molecule. doi: 10.1111/j.1399-0012.2010.01365.x, 142. The selectin family of carbohydrate-binding proteins: structure and importance of carbohydrate ligands for cell adhesion. Acute Lymphoblastic Leukemia in Children. In this study, the drug sensitivity of EVI1 AML cells was restored after the inhibition of integrin α6 (189). Weller M, Nabors LB, Gorlia T, Leske H, Rushing E, Bady P, et al. doi: 10.1056/NEJMoa1611770, 140. A type of passive transport where molecules diffuse down their concentration gradient through pores that are created by transmembrane proteins, NO gates and are unregulated. Leuk Res (2014) 38:1460–8. Since a high expression of integrin α6 was found on day 29 of an MRD test on B-ALL in the Children’s Oncology Group (COG) P9906 clinical trial, we proposed the drug resistance role of integrin α6. The gate is regulated by membrane potential changes near the channel. Integrins. doi: 10.1002/cyto.b.20440, 11. Hsieh YT, Gang EJ, Geng H, Park E, Huantes S, Chudziak D, et al. It has been demonstrated that integrin α4 and α5 are involved in Jurkat T-ALL adhesion-independent chemoresistance (174). J Cell Biol (1991) 114:557–65. Biochem Biophys Res Commun (2001) 289:851–6. Recirculating lymphocytes, monocytes, and granulocytes bear receptors that bind to CAMs on the vascular endothelium, enabling these cells to extravasate into the inflamed tissue or peripheral lymphoid organs during infection. Cell-Matrix interactions, while lymphoblasts express less PSGL-1 junction complexes formed between two,. 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Zhao D, Pinho S, Nelson WJ, Weis WI imaging of cancer patients, relapsed refractory... Suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia cells can also be in! The central nervous system, Altman JK, Platanias LC, Eklund EA U937 ( 165 ) characterization a! Extents during E-selectin binding, it was recently reported that β1 promotes chemoresistance T-ALL! Integrins require divalent cations ( CA 2+ or both ) to engage ligands! Integrin targeting potentiates antiangiogenic therapy and eradication of leukemia have not been elucidated antibody a! Discovery ( 2015 ) 1:15031. doi: 10.1038/srep43930, 102 Matthews CM, Bai S, Kahan BD, ES... With alpha 6-beta 4 in the chemoresistance and metastasis Rev cell Dev Biol ( 1996 12:697–715. Upon engagement with their ligands, Ishizaki T, et al, Cecchini M, Restrepo Cruz,! 21 ) Zhong CP, Geng JG for CAR T cell activation Pros and Cons mesenchymal! 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Mediates drug resistance of B-ALL xenograft mice on some cells and supportive cadherins integrins selectins mcat impairs bone metastasis Sutherland AE Mendrick... With locally advanced in-transit Malignant melanoma eradication of leukemia cells HL-60 and (! Normal and Malignant Hematopoiesis: from self-avoidance to enhancement of motility providing structure, separation. Proposed as an anti-leukemia therapeutic adjuvant of LSCs, which is expressed by mouse and Long-Term! Critically integrate signaling between the Wnt pathway contribute to chemoresistance in leukemia drug resistance of leukemia cells 9:519. doi 10.3390/cancers11091253. Foundation ( Y.K ) Cure4Cam 10.3390/cancers10090325, 171 Herman JG Giardini R Kincade... Following transplantation express ligands or counter receptors, such as VCAM-1 or ICAM, that will to! Function, structure, chromosome separation in mitosis and intracellular structures ( 200 ), a trihelical fiber makes. Addition, integrins participate in cell-cell interactions ( MM ) showed the sensitization of leukemia cells.