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Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Review Article

Obesity and Cathepsin K: A Complex Pathophysiological Relationship in Breast Cancer Metastases

Author(s): Yaongamphi Vashum* and Zenith Khashim

Volume 20, Issue 8, 2020

Page: [1227 - 1231] Pages: 5

DOI: 10.2174/1871530320666200505115132

Price: $65

Abstract

Background: Breast cancer appears in a strong inclination to metastasize in bone tissue. Several strategies are discussed in combating bone metastasis in breast cancer. However, therapy is only palliative and does not provide any improvement in survival to the majority of patients with advanced cancer. Obese and overweight women with breast cancer are three times more likely to develop metastatic disease compared to normal-weight women with the same treatment regimen. Overweight greatly intensify adipocytes formation in the bone marrow affecting bone metabolism by decreasing osteoblast differentiation and bone formation. Cathepsin K (CTSK), a cysteine protease, effectively degrades several components of the extracellular matrix and has the ability to differentiate adipocytes from bone marrow lineage. Therefore, the purpose of this review is to emphasize the underlying mechanism of CTSK and obesity role in breast cancer metastasis.

Methods: Systematic review was performed using PubMed, EMBASE. The evidence of obesity and CTSK in breast cancer skeletal metastasis were analyzed, summarized and compared.

Results: The present investigation argues for a specific association of CTSK with breast cancer skeletal metastasis by promoting adipocyte differentiation. The potential tumor-supporting roles of adipocytes are well documented, and in fact, suppressing adipocyte could be a new therapeutic option in the battle against lethal metastatic breast cancers.

Conclusion: This review emphasizes CTSK through its multifaceted role in differentiating adipocytes, inflammation, and extracellular degradation, may be a critical factor in an obesity-cancer connection. Thus, integration of CTSK targeting strategies into established traditional therapies seems to hold substantial promise.

Keywords: Breast cancer, cathepsin K, obesity, adipocytes, metastates, pathophysiological relationship.

Graphical Abstract

[1]
De, S.; Chen, J.; Narizhneva, N.V.; Heston, W.; Brainard, J.; Sage, E.H.; Byzova, T.V. Molecular pathway for cancer metastasis to bone. J. Biol. Chem., 2003, 278(40), 39044-39050.
[http://dx.doi.org/10.1074/jbc.M304494200] [PMID: 12885781]
[2]
Ishikawa, M.; Kitayama, J.; Nagawa, H. Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin. Cancer Res., 2004, 10(13), 4325-4331.
[http://dx.doi.org/10.1158/1078-0432.CCR-03-0749] [PMID: 15240518]
[3]
Jacob, K.; Webber, M.; Benayahu, D.; Kleinman, H.K. Osteonectin promotes prostate cancer cell migration and invasion: A possible mechanism for metastasis to bone. Cancer Res., 1999, 59(17), 4453-4457.
[PMID: 10485497]
[4]
Brubaker, K.D.; Vessella, R.L.; True, L.D.; Thomas, R.; Corey, E. Cathepsin K mRNA and protein expression in prostate cancer progression. J. Bone Miner. Res., 2003, 18(2), 222-230.
[http://dx.doi.org/10.1359/jbmr.2003.18.2.222] [PMID: 12568399]
[5]
Podgorski, I.; Linebaugh, B.E.; Sloane, B.F. Cathepsin K in the bone microenvironment: Link between obesity and prostate cancer. Biochem Soc Trans, 2007, 35(Pt 4), 701-703.
[PMID: 17635127]
[6]
Chang, S.H.; Kanasaki, K.; Gocheva, V.; Blum, G.; Harper, J.; Moses, M.A.; Shih, S.C.; Nagy, J.A.; Joyce, J.; Bogyo, M.; Kalluri, R.; Dvorak, H.F. VEGF-A induces angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation. Cancer Res., 2009, 69(10), 4537-4544.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4539] [PMID: 19435903]
[7]
Garnero, P.; Buchs, N.; Zekri, J.; Rizzoli, R.; Coleman, R.E.; Delmas, P.D. Markers of bone turnover for the management of patients with bone metastases from prostate cancer. Br. J. Cancer, 2000, 82(4), 858-864.
[http://dx.doi.org/10.1054/bjoc.1999.1012] [PMID: 10732759]
[8]
Littlewood-Evans, A.J.; Bilbe, G.; Bowler, W.B.; Farley, D.; Wlodarski, B.; Kokubo, T.; Inaoka, T.; Sloane, J.; Evans, D.B.; Gallagher, J.A. The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res., 1997, 57(23), 5386-5390.
[PMID: 9393764]
[9]
Podhajcer, OL; Benedetti, LG; Girotti, MR; Prada, F; Salvatierra, E; Llera, A.S. The role of the matricellular protein SPARC in the dynamic interaction between the tumor and the host. Cancer Metastasis Rev, 2008, 27(4), 691-705.
[http://dx.doi.org/10.1007/s10555-008-9146-7] [PMID: 18542844]
[10]
Said, N.; Frierson, H.F., Jr.; Chernauskas, D.; Conaway, M.; Motamed, K.; Theodorescu, D. The role of SPARC in the TRAMP model of prostate carcinogenesis and progression. Oncogene, 2009, 28(39), 3487-3498.
[http://dx.doi.org/10.1038/onc.2009.205] [PMID: 19597474]
[11]
Chlenski, A.; Cohn, S.L. Modulation of matrix remodeling by SPARC in neoplastic progression. Semin Cell Dev. Biol., 2010, 21(1), 55-65.
[http://dx.doi.org/10.1016/j.semcdb.2009.11.018] [PMID: 19958839]
[12]
Said, N.; Frierson, H.F.; Sanchez-Carbayo, M.; Brekken, R.A.; Theodorescu, D. Loss of SPARC in bladder cancer enhances carcinogenesis and progression. J. Clin. Invest., 2013, 123(2), 751-766.
[http://dx.doi.org/10.1172/JCI64782] [PMID: 23321672]
[13]
Shin, M.; Mizokami, A.; Kim, J.; Ofude, M.; Konaka, H.; Kadono, Y.; Kitagawa, Y.; Miwa, S.; Kumaki, M.; Keller, E.T.; Namiki, M. Exogenous SPARC suppresses proliferation and migration of prostate cancer by interacting with integrin β1. Prostate, 2013, 73(11), 1159-1170.
[http://dx.doi.org/10.1002/pros.22664] [PMID: 23532895]
[14]
Podgorski, I.; Linebaugh, B.E.; Koblinski, J.E.; Rudy, D.L.; Herroon, M.K.; Olive, M.B.; Sloane, B.F. Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. Am. J. Pathol., 2009, 175(3), 1255-1269.
[http://dx.doi.org/10.2353/ajpath.2009.080906] [PMID: 19700761]
[15]
Ribeiro, N.; Sousa, S.R.; Brekken, R.A.; Monteiro, F.J. Role of SPARC in bone remodeling and cancer-related bone metastasis. J. Cell. Biochem., 2014, 115(1), 17-26.
[http://dx.doi.org/10.1002/jcb.24649] [PMID: 24038053]
[16]
Sharma, S.; Xing, F.; Liu, Y.; Wu, K.; Said, N.; Pochampally, R.; Shiozawa, Y.; Lin, H.K.; Balaji, K.C.; Watabe, K. Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone. J. Biol. Chem., 2016, 291(37), 19351-19363.
[http://dx.doi.org/10.1074/jbc.M116.737379] [PMID: 27422817]
[17]
Graham, J.D.; Balleine, R.L.; Milliken, J.S.; Bilous, A.M.; Clarke, C.L. Expression of osteonectin mRNA in human breast tumours is inversely correlated with oestrogen receptor content. Eur. J. Cancer, 1997, 33(10), 1654-1660.
[http://dx.doi.org/10.1016/S0959-8049(97)00182-2] [PMID: 9389930]
[18]
Hsiao, Y.H.; Lien, H.C.; Hwa, H.L.; Kuo, W.H.; Chang, K.J.; Hsieh, F.J. SPARC (osteonectin) in breast tumors of different histologic types and its role in the outcome of invasive ductal carcinoma. Breast J., 2010, 16(3), 305-308.
[http://dx.doi.org/10.1111/j.1524-4741.2009.00899.x] [PMID: 20210803]
[19]
Nagai, M.A.; Gerhard, R.; Fregnani, J.H.; Nonogaki, S.; Rierger, R.B.; Netto, M.M.; Soares, F.A. Prognostic value of NDRG1 and SPARC protein expression in breast cancer patients. Breast Cancer Res. Treat., 2011, 126(1), 1-14.
[http://dx.doi.org/10.1007/s10549-010-0867-2] [PMID: 20369286]
[20]
Rahman, M.; Chan, A.P.; Tang, M.; Tai, I.T. A peptide of SPARC interferes with the interaction between caspase8 and Bcl2 to resensitize chemoresistant tumors and enhance their regression in vivo. PLoS One, 2011, 6(11), e26390.
[http://dx.doi.org/10.1371/journal.pone.0026390] [PMID: 22069448]
[21]
Trujillo, K.A.; Heaphy, C.M.; Mai, M.; Vargas, K.M.; Jones, A.C.; Vo, P.; Butler, K.S.; Joste, N.E.; Bisoffi, M.; Griffith, J.K. Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. Int. J. Cancer, 2011, 129(6), 1310-1321.
[http://dx.doi.org/10.1002/ijc.25788] [PMID: 21105047]
[22]
Witkiewicz, A.K.; Freydin, B.; Chervoneva, I.; Potoczek, M.; Rizzo, W.; Rui, H.; Brody, J.R.; Schwartz, G.F.; Lisanti, M.P. Stromal CD10 and SPARC expression in ductal carcinoma in situ (DCIS) patients predicts disease recurrence. Cancer Biol. Ther., 2010, 10(4), 391-396.
[http://dx.doi.org/10.4161/cbt.10.4.12449] [PMID: 20574156]
[23]
Lane, T.F.; Iruela-Arispe, M.L.; Johnson, R.S.; Sage, E.H. SPARC is a source of copper-binding peptides that stimulate angiogenesis. J. Cell Biol., 1994, 125(4), 929-943.
[http://dx.doi.org/10.1083/jcb.125.4.929] [PMID: 7514608]
[24]
Sasaki, T.; Göhring, W.; Mann, K.; Maurer, P.; Hohenester, E.; Knäuper, V.; Murphy, G.; Timpl, R. Limited cleavage of extracellular matrix protein BM-40 by matrix metalloproteinases increases its affinity for collagens. J. Biol. Chem., 1997, 272(14), 9237-9243.
[http://dx.doi.org/10.1074/jbc.272.14.9237] [PMID: 9083057]
[25]
McCabe, N.P.; Kerr, B.A.; Madajka, M.; Vasanji, A.; Byzova, T.V. Augmented osteolysis in SPARC-deficient mice with bone-residing prostate cancer. Neoplasia, 2011, 13(1), 31-39.
[http://dx.doi.org/10.1593/neo.10998] [PMID: 21245938]
[26]
Mateo, F.; Meca-Cortés, O.; Celià-Terrassa, T.; Fernández, Y.; Abasolo, I.; Sánchez-Cid, L.; Bermudo, R.; Sagasta, A.; Rodríguez-Carunchio, L.; Pons, M.; Cánovas, V.; Marín-Aguilera, M.; Mengual, L.; Alcaraz, A.; Schwartz, S., Jr; Mellado, B.; Aguilera, K.Y.; Brekken, R.; Fernández, P.L.; Paciucci, R.; Thomson, T.M. SPARC mediates metastatic cooperation between CSC and non-CSC prostate cancer cell subpopulations. Mol. Cancer, 2014, 13, 237.
[http://dx.doi.org/10.1186/1476-4598-13-237] [PMID: 25331979]
[27]
Nagaraju, GP; Dontula, R; El-Rayes, BF; Lakka, SS Molecular mechanisms underlying the divergent roles of SPARC in human carcinogenesis. Carcinogenesis, 2014, 35(5), 967-73.
[http://dx.doi.org/10.1093/carcin/bgu072] [PMID: 24675529]
[28]
Koblinski, J.E.; Kaplan-Singer, B.R.; VanOsdol, S.J.; Wu, M.; Engbring, J.A.; Wang, S.; Goldsmith, C.M.; Piper, J.T.; Vostal, J.G.; Harms, J.F.; Welch, D.R.; Kleinman, H.K. Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis. Cancer Res., 2005, 65(16), 7370-7377.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-0807] [PMID: 16103089]
[29]
Bielenberg, D.R.; Zetter, B.R. The contribution of angiogenesis to the process of metastasis. Cancer J., 2015, 21(4), 267-273.
[http://dx.doi.org/10.1097/PPO.0000000000000138] [PMID: 26222078]
[30]
Henriksen, K.; Karsdal, M.; Delaisse, J.M.; Engsig, M.T. RANKL and vascular endothelial growth factor (VEGF) induce osteoclast chemotaxis through an ERK1/2-dependent mechanism. J. Biol. Chem., 2003, 278(49), 48745-48753.
[http://dx.doi.org/10.1074/jbc.M309193200] [PMID: 14506249]
[31]
Ryschich, E.; Lizdenis, P.; Ittrich, C.; Benner, A.; Stahl, S.; Hamann, A.; Schmidt, J.; Knolle, P.; Arnold, B.; Hämmerling, G.J.; Ganss, R. Molecular fingerprinting and autocrine growth regulation of endothelial cells in a murine model of hepatocellular carcinoma. Cancer Res., 2006, 66(1), 198-211.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1636] [PMID: 16397233]
[32]
Joyce, J.A.; Baruch, A.; Chehade, K.; Meyer-Morse, N.; Giraudo, E.; Tsai, F.Y.; Greenbaum, D.C.; Hager, J.H.; Bogyo, M.; Hanahan, D. Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell, 2004, 5(5), 443-453.
[http://dx.doi.org/10.1016/S1535-6108(04)00111-4] [PMID: 15144952]
[33]
Bremer, C.; Tung, C.H.; Weissleder, R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat. Med., 2001, 7(6), 743-748.
[http://dx.doi.org/10.1038/89126] [PMID: 11385514]
[34]
Tung, C.H.; Mahmood, U.; Bredow, S.; Weissleder, R. In vivo imaging of proteolytic enzyme activity using a novel molecular reporter. Cancer Res., 2000, 60(17), 4953-4958.
[PMID: 10987312]
[35]
Steeg, PS Tumor metastasis: mechanistic insights and clinical challenges. Nat Med, 2006, 12(8), 895-904.
[http://dx.doi.org/10.1038/nm1469] [PMID: 16892035]
[36]
Choi, J; Cha, YJ; Koo, JS Adipocyte biology in breast cancer: From silentbystander to active facilitator. Prog Lipid Res, 2018, 69, 11-20.
[http://dx.doi.org/10.1016/j.plipres.2017.11.002] [PMID: 29175445]
[37]
He, J.Y.; Wei, X.H.; Li, S.J.; Liu, Y.; Hu, H.L.; Li, Z.Z.; Kuang, X.H.; Wang, L.; Shi, X.; Yuan, S.T.; Sun, L. Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression. Cell Commun. Signal., 2018, 16(1), 100.
[http://dx.doi.org/10.1186/s12964-018-0309-z] [PMID: 30563531]
[38]
Zavasnik-Bergant, T.; Turk, B. Cysteine cathepsins in the immune response. Tissue Antigens, 2006, 67(5), 349-55.
[http://dx.doi.org/10.1111/j.1399-0039.2006.00585.x] [PMID: 16671941]
[39]
Jacobson, L.S.; Lima, H., Jr; Goldberg, M.F.; Gocheva, V.; Tsiperson, V.; Sutterwala, F.S.; Joyce, J.A.; Gapp, B.V.; Blomen, V.A.; Chandran, K.; Brummelkamp, T.R.; Diaz-Griffero, F.; Brojatsch, J. Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants. J. Biol. Chem., 2013, 288(11), 7481-7491.
[http://dx.doi.org/10.1074/jbc.M112.400655] [PMID: 23297415]
[40]
Hao, L.; Zhu, G.; Lu, Y.; Wang, M.; Jules, J.; Zhou, X.; Chen, W. Deficiency of cathepsin K prevents inflammation and bone erosion in rheumatoid arthritis and periodontitis and reveals its shared osteoimmune role. FEBS Lett., 2015, 589(12), 1331-1339.
[http://dx.doi.org/10.1016/j.febslet.2015.04.008] [PMID: 25896020]
[41]
Huang, B.; Zhao, J.; Li, H.; He, K.L.; Chen, Y.; Chen, S.H.; Mayer, L.; Unkeless, J.C.; Xiong, H. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res., 2005, 65(12), 5009-5014.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-0784] [PMID: 15958541]
[42]
Yang, H.; Wang, B.; Wang, T.; Xu, L.; He, C.; Wen, H.; Yan, J.; Su, H.; Zhu, X. Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis. PLoS One, 2014, 9(10), e109980.
[http://dx.doi.org/10.1371/journal.pone.0109980] [PMID: 25299052]
[43]
Gyamfi, J. Multifaceted roles of interleukin-6 in adipocyte-breast cancer interaction. Transl Oncol, 2018, 11(2), 275285.
[http://dx.doi.org/10.1016/j.tranon.2017.12.009] [PMID: 29413760]
[44]
Asagiri, M.; Hirai, T.; Kunigami, T.; Kamano, S.; Gober, H.J.; Okamoto, K.; Nishikawa, K.; Latz, E.; Golenbock, D.T.; Aoki, K.; Ohya, K.; Imai, Y.; Morishita, Y.; Miyazono, K.; Kato, S.; Saftig, P.; Takayanagi, H. Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science, 2008, 319(5863), 624-627.
[http://dx.doi.org/10.1126/science.1150110] [PMID: 18239127]
[45]
Yusuf, N. Toll-like receptor mediated regulation of breast cancer: A case of mixed blessings. Front. Immunol., 2014, 5, 224.
[http://dx.doi.org/10.3389/fimmu.2014.00224] [PMID: 24904578]
[46]
Hao, L.; Chen, J.; Zhu, Z.; Reddy, M.S.; Mountz, J.D.; Chen, W.; Li, Y.P. Odanacatib, A Cathepsin K-specific inhibitor, inhibits inflammation and bone loss caused by periodontal diseases. J. Periodontol., 2015, 86(8), 972-983.
[http://dx.doi.org/10.1902/jop.2015.140643] [PMID: 25879791]
[47]
Luo, G.; He, Y.; Yu, X. Bone marrow adipocyte: An intimate partner with tumor cells in bone metastasis. Front Endocrinol (Lausanne)., 2018 June;229(), 339.
[http://dx.doi.org/10.3389/fendo.2018.00339 ] [PMID: 30013512]
[48]
Hardaway, A.L.; Herroon, M.K.; Rajagurubandara, E.; Podgorski, I. Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases. Cancer Metastasis Rev., 2014, 33(2-3), 527-543.
[http://dx.doi.org/10.1007/s10555-013-9484-y] [PMID: 24398857]
[49]
Pathania, S; Bhatia, R; Baldi, A; Singh, R; Rawal, RK Drug metabolizing enzymes and their inhibitors’ role in cancer resistance. Biomed. Pharmacother., 2018, 105, 53-65.
[http://dx.doi.org/10.1016/j.biopha.2018.05.117] [PMID: 29843045]
[50]
Ratajczak, M.Z.; Jadczyk, T.; Schneider, G.; Kakar, S.S.; Kucia, M. Induction of a tumor-metastasis-receptive microenvironment as an unwanted and underestimated side effect of treatment by chemotherapy or radiotherapy. J. Ovarian Res., 2013, 6(1), 95.
[http://dx.doi.org/10.1186/1757-2215-6-95] [PMID: 24373588]

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