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Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment


We have identified a new role for the matrix enzyme lysyl oxidase–like-2 (LOXL2) in the creation and maintenance of the pathologic microenvironment of cancer and fibrotic disease. Our analysis of biopsies from human tumors and fibrotic lung and liver tissues revealed an increase in LOXL2 in disease-associated stroma and limited expression in healthy tissues. Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models. Inhibition of LOXL2 resulted in a marked reduction in activated fibroblasts, desmoplasia and endothelial cells, decreased production of growth factors and cytokines and decreased transforming growth factor-β (TGF-β) pathway signaling. AB0023 outperformed the small-molecule lysyl oxidase inhibitor β-aminoproprionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncologic and fibrotic diseases.

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Figure 1: LOXL2 localization in the stroma of diverse tumor types.
Figure 2: In vitro characterization of inhibitory monoclonal antibody AB0023.
Figure 3: Effects of AB0023 on fibroblast activation and growth factor abundance in the tumor microenvironment.
Figure 4: Comparison of AB0023 and β-APN and effects of AB0023 on metastatic burden in xenograft models.
Figure 5: Effects of AB0023 in a liver fibrosis model.
Figure 6: Effects of AB0023 in bleomycin-induced lung fibrosis.


  1. 1

    Barcellos-Hoff, M.H. & Ravani, S.A. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res. 60, 1254–1260 (2000).

    CAS  PubMed  Google Scholar 

  2. 2

    Bhowmick, N.A., Neilson, E.G. & Moses, H.L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).

    CAS  Article  Google Scholar 

  3. 3

    Coussens, L.M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    CAS  Article  Google Scholar 

  4. 4

    Cunha, G.R., Hayward, S.W., Wang, Y.Z. & Ricke, W.A. Role of the stromal microenvironment in carcinogenesis of the prostate. Int. J. Cancer 107, 1–10 (2003).

    CAS  Article  Google Scholar 

  5. 5

    Jacobs, T.W., Byrne, C., Colditz, G., Connolly, J.L. & Schnitt, S.J. Radial scars in benign breast-biopsy specimens and the risk of breast cancer. N. Engl. J. Med. 340, 430–436 (1999).

    CAS  Article  Google Scholar 

  6. 6

    Olumi, A.F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  Google Scholar 

  7. 7

    Orimo, A. et al. Cancer-associated myofibroblasts possess various factors to promote endometrial tumor progression. Clin. Cancer Res. 7, 3097–3105 (2001).

    CAS  PubMed  Google Scholar 

  8. 8

    Kleeff, J. et al. Pancreatic cancer microenvironment. Int. J. Cancer 121, 699–705 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Cardone, A., Tolino, A., Zarcone, R., Borruto Caracciolo, G. & Tartaglia, E. Prognostic value of desmoplastic reaction and lymphocytic infiltration in the management of breast cancer. Panminerva Med. 39, 174–177 (1997).

    CAS  PubMed  Google Scholar 

  10. 10

    Chu, G.C., Kimmelman, A.C., Hezel, A.F. & DePinho, R.A. Stromal biology of pancreatic cancer. J. Cell. Biochem. 101, 887–907 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Conti, J.A. et al. The desmoplastic reaction surrounding hepatic colorectal adenocarcinoma metastases aids tumor growth and survival via alphav integrin ligation. Clin. Cancer Res. 14, 6405–6413 (2008).

    CAS  Article  Google Scholar 

  12. 12

    Maeshima, A.M. et al. Modified scar grade: a prognostic indicator in small peripheral lung adenocarcinoma. Cancer 95, 2546–2554 (2002).

    Article  Google Scholar 

  13. 13

    Sappino, A.P., Skalli, O., Jackson, B., Schurch, W. & Gabbiani, G. Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues. Int. J. Cancer 41, 707–712 (1988).

    CAS  Article  Google Scholar 

  14. 14

    Dong, J. et al. VEGF-null cells require PDGFRα signaling–mediated stromal fibroblast recruitment for tumorigenesis. EMBO J. 23, 2800–2810 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Hinz, B. et al. The myofibroblast: one function, multiple origins. Am. J. Pathol. 170, 1807–1816 (2007).

    CAS  Article  Google Scholar 

  16. 16

    Hlatky, L., Tsionou, C., Hahnfeldt, P. & Coleman, C.N. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res. 54, 6083–6086 (1994).

    CAS  PubMed  Google Scholar 

  17. 17

    Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Butcher, D.T., Alliston, T. & Weaver, V.M. A tense situation: forcing tumour progression. Nat. Rev. Cancer 9, 108–122 (2009).

    CAS  Article  Google Scholar 

  19. 19

    Georges, P.C. et al. Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G1147–G1154 (2007).

    CAS  Article  Google Scholar 

  20. 20

    Levental, K.R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Wipff, P.J., Rifkin, D.B., Meister, J.J. & Hinz, B. Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).

    CAS  Article  Google Scholar 

  22. 22

    Suki, B., Ito, S., Stamenovic, D., Lutchen, K.R. & Ingenito, E.P. Biomechanics of the lung parenchyma: critical roles of collagen and mechanical forces. J. Appl. Physiol. 98, 1892–1899 (2005).

    Article  Google Scholar 

  23. 23

    Kagan, H.M. & Li, W. Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J. Cell. Biochem. 88, 660–672 (2003).

    CAS  Article  Google Scholar 

  24. 24

    Payne, S.L., Hendrix, M.J. & Kirschmann, D.A. Paradoxical roles for lysyl oxidases in cancer—a prospect. J. Cell. Biochem. 101, 1338–1354 (2007).

    CAS  Article  Google Scholar 

  25. 25

    Vadasz, Z. et al. Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J. Hepatol. 43, 499–507 (2005).

    CAS  Article  Google Scholar 

  26. 26

    Erler, J.T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Akiri, G. et al. Lysyl oxidase–related protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res. 63, 1657–1666 (2003).

    CAS  PubMed  Google Scholar 

  28. 28

    Fong, S.F. et al. Lysyl oxidase–like 2 expression is increased in colon and esophageal tumors and associated with less differentiated colon tumors. Genes Chromosom. Cancer 46, 644–655 (2007).

    CAS  Article  Google Scholar 

  29. 29

    Hollosi, P., Yakushiji, J.K., Fong, K.S., Csiszar, K. & Fong, S.F. Lysyl oxidase–like 2 promotes migration in noninvasive breast cancer cells but not in normal breast epithelial cells. Int. J. Cancer 125, 318–327 (2009).

    CAS  Article  Google Scholar 

  30. 30

    Kirschmann, D.A. et al. A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res. 62, 4478–4483 (2002).

    CAS  PubMed  Google Scholar 

  31. 31

    Peng, L. et al. Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway. Carcinogenesis 30, 1660–1669 (2009).

    CAS  Article  Google Scholar 

  32. 32

    Rodriguez, H.M. et al. Modulation of lysyl oxidase–like 2 enzymatic activity by an allosteric antibody inhibitor. J. Biol. Chem. 285, 20964–20974 (2010).

    CAS  Article  Google Scholar 

  33. 33

    Peinado, H. et al. A molecular role for lysyl oxidase–like 2 enzyme in snail regulation and tumor progression. EMBO J. 24, 3446–3458 (2005).

    CAS  Article  Google Scholar 

  34. 34

    Lelièvre, E. et al. VE-statin/egfl7 regulates vascular elastogenesis by interacting with lysyl oxidases. EMBO J. 27, 1658–1670 (2008).

    Article  Google Scholar 

  35. 35

    Chambers, A.F. MDA-MB-435 and M14 cell lines: identical but not M14 melanoma? Cancer Res. 69, 5292–5293 (2009).

    CAS  Article  Google Scholar 

  36. 36

    Yang, F. et al. Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis. Cancer Res. 65, 8887–8895 (2005).

    CAS  Article  Google Scholar 

  37. 37

    Gozuacik, D. & Kimchi, A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23, 2891–2906 (2004).

    CAS  Article  Google Scholar 

  38. 38

    Tang, S.S., Trackman, P.C. & Kagan, H.M. Reaction of aortic lysyl oxidase with beta-aminopropionitrile. J. Biol. Chem. 258, 4331–4338 (1983).

    CAS  PubMed  Google Scholar 

  39. 39

    Trackman, P.C. & Kagan, H.M. Nonpeptidyl amine inhibitors are substrates of lysyl oxidase. J. Biol. Chem. 254, 7831–7836 (1979).

    CAS  PubMed  Google Scholar 

  40. 40

    Jenkins, D.E., Hornig, Y.S., Oei, Y., Dusich, J. & Purchio, T. Bioluminescent human breast cancer cell lines that permit rapid and sensitive in vivo detection of mammary tumors and multiple metastases in immune deficient mice. Breast Cancer Res. 7, R444–R454 (2005).

    CAS  Article  Google Scholar 

  41. 41

    The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 20, 15–20 (1994).

  42. 42

    Tahashi, Y. et al. Differential regulation of TGF-β signal in hepatic stellate cells between acute and chronic rat liver injury. Hepatology 35, 49–61 (2002).

    CAS  Article  Google Scholar 

  43. 43

    Inagaki, Y. et al. Constitutive phosphorylation and nuclear localization of Smad3 are correlated with increased collagen gene transcription in activated hepatic stellate cells. J. Cell. Physiol. 187, 117–123 (2001).

    CAS  Article  Google Scholar 

  44. 44

    Khalil, N. & O'Connor, R. Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment. CMAJ 171, 153–160 (2004).

    Article  Google Scholar 

  45. 45

    Moeller, A., Ask, K., Warburton, D., Gauldie, J. & Kolb, M. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int. J. Biochem. Cell Biol. 40, 362–382 (2008).

    CAS  Article  Google Scholar 

  46. 46

    Ashcroft, T., Simpson, J.M. & Timbrell, V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J. Clin. Pathol. 41, 467–470 (1988).

    CAS  Article  Google Scholar 

  47. 47

    Moeller, A. et al. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 179, 588–594 (2009).

    Article  Google Scholar 

  48. 48

    Park, S.H., Saleh, D., Giaid, A. & Michel, R.P. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am. J. Respir. Crit. Care Med. 156, 600–608 (1997).

    CAS  Article  Google Scholar 

  49. 49

    Pulichino, A.M. et al. Identification of transforming growth factor beta1-driven genetic programs of acute lung fibrosis. Am. J. Respir. Cell Mol. Biol. 39, 324–336 (2008).

    CAS  Article  Google Scholar 

  50. 50

    Xu, J. et al. Role of the SDF-1/CXCR4 axis in the pathogenesis of lung injury and fibrosis. Am. J. Respir. Cell Mol. Biol. 37, 291–299 (2007).

    CAS  Article  Google Scholar 

  51. 51

    Dornhöfer, N. et al. Connective tissue growth factor–specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 66, 5816–5827 (2006).

    Article  Google Scholar 

  52. 52

    Guleng, B. et al. Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor–independent manner. Cancer Res. 65, 5864–5871 (2005).

    CAS  Article  Google Scholar 

  53. 53

    Bailey, J.M. et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin. Cancer Res. 14, 5995–6004 (2008).

    CAS  Article  Google Scholar 

  54. 54

    Van Aarsen, L.A. et al. Antibody-mediated blockade of integrin αvβ6 inhibits tumor progression in vivo by a transforming growth factor-β–regulated mechanism. Cancer Res. 68, 561–570 (2008).

    Article  Google Scholar 

  55. 55

    Ge, R. et al. Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-β type I receptor kinase in vivo. Clin. Cancer Res. 12, 4315–4330 (2006).

    CAS  Article  Google Scholar 

  56. 56

    Nam, J.S. et al. An anti-transforming growth factor β antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res. 68, 3835–3843 (2008).

    CAS  Article  Google Scholar 

  57. 57

    Qiu, W. et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat. Genet. 40, 650–655 (2008).

    CAS  Article  Google Scholar 

  58. 58

    Constandinou, C., Henderson, N. & Iredale, J.P. Modeling liver fibrosis in rodents. Methods Mol. Med. 117, 237–250 (2005).

    PubMed  Google Scholar 

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We thank S. Lyle for guidance and interpretation of tissue pathology and J. Adamkewicz, S. Lyle, M. Longaker and F. McCormick for their review of this manuscript. We thank G. Rosen and J. Belperio for guidance with bleomycin-induced lung fibrosis studies and G. Gurtner for help with wound-healing study design. We thank J. Tambaoan for program support.

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V.B.-H. and R.S. performed immunohistochemistry and histology on human and mouse tissues and all associated analyses, with V.B.-H. leading the immunohistochemistry group, and they both participated in manuscript preparation. V.B.-H. performed EMT studies, D.M. performed transcript analyses, managed the tissue collection, designed the wound-healing model and participated in manuscript preparation, S.M. performed cloning and expression and participated in EMT experiments and manuscript preparation, H.M.R. performed data analysis, IC50 studies and antibody characterization, M.O. performed immunohistochemistry and analysis for the liver fibrosis study, A.M. and M.V. performed tension experiments and antibody characterization, A.M. participated in manuscript preparation, H.G. performed immunohistochemistry analysis for the SKOV3 study and participated in manuscript preparation, C.W. performed transcript analysis, C.A.G., A.C.V., B.J., D.B. and D.T. generated, characterized and quality controlled all antibodies and proteins under the leadership of C.A.G., J.G. performed tissue ELISA, S.Z.-E. contributed to antibody characterization and performed the microvessel density analysis, A.H. supervised the MDA-MB-435 mouse studies, S.O. assisted with the management of contract research groups, D.T. participated in toxicology studies and manuscript preparation, G.N. developed the Y698F mutant and contributed to oncology studies and manuscript preparation, P.V.V. participated in experimental design and manuscript preparation and V.S. designed the metastasis, fibrosis and toxicology animal studies and analyses, supervised the experimental work and wrote the paper.

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Correspondence to Victoria Smith.

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As current or former employees of Arresto BioSciences, V.B.-H., R.S., D.M., S.M., H.M.R., M.O., A.M., M.V., H.G., C.W., C.A.G., A.C.V., B.J., D.B., D.T., A.H., S.O., D.T., P.V.V. & V.S. have an equity stake in the company.

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Barry-Hamilton, V., Spangler, R., Marshall, D. et al. Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment. Nat Med 16, 1009–1017 (2010).

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