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Open Access 01-12-2018 | Research article

The bone microenvironment promotes tumor growth and tissue perfusion compared with striated muscle in a preclinical model of prostate cancer in vivo

Authors: Haider Mussawy, Lennart Viezens, Malte Schroeder, Svenja Hettenhausen, Jördis Sündermann, Jasmin Wellbrock, Kai Kossow, Christian Schaefer

Published in: BMC Cancer | Issue 1/2018

Abstract

Background

Prostate cancer-related morbidity is associated with its preferential spread to the bone. Although the molecular interactions between the bone microenvironment and cancer cells have been researched extensively, the relevance of the microvascular properties of prostate cancer bone metastases remains largely unknown. Most preclinical studies focusing on microvascular analyses are based on heterotopic tumor implantation, whereas the impact of the microenvironment on site-specific growth behavior and angiogenesis is rarely addressed.

Methods

The microvascular changes associated with tumor growth in bone and soft tissue were characterized by implanting single cell suspensions of LnCap, Du145, and Pc3 cells into the femur (femur window) or striated muscle (dorsal skinfold chamber) of NSG mice. Tumor growth and the local microvasculature were analyzed for 21 days using intravital fluorescence microscopy.

Results

The results showed a higher engraftment of tumor cells in bone than in striated muscle associated with accelerated growth of LnCap cells and Pc3 cells. Permeability, blood flow, and tissue perfusion rates were greater in bone than in striated muscle. Du145 cells showed similar growth behavior in both tissues with similar vascular properties. The bone microenvironment facilitated tumor engraftment and growth. Increased microvascular density in striated muscle led to a higher tumor burden during early growth, whereas the increased perfusion promoted later prostate cancer growth in bone.

Conclusions

Monitoring prostate cancer microcirculation in bone and soft tissue may be useful to evaluate the organ-specific efficacy of new treatments.

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Jemal A, Fedewa SA, Ma J, Siegel R, Lin CC, Brawley O, et al. Prostate Cancer incidence and PSA testing patterns in relation to USPSTF screening recommendations. JAMA 2015;314(19):2054–2061. https://doi.org/10.1001/jama.2015.14905. PubMed PMID: 26575061.CrossRef

Wang N, Docherty FE, Brown HK, Reeves KJ, Fowles AC, Ottewell PD, et al. Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis: evidence from in vivo models. J Bone Miner Res 2014;29(12):2688–2696. https://doi.org/10.1002/jbmr.2300. PubMed PMID: 24956445.CrossRef

Keyes KA, Mann L, Teicher B, Alvarez E. Site-dependent angiogenic cytokine production in human tumor xenografts. Cytokine 2003;21(2):98–104. PubMed PMID: 12670449.CrossRef

Fukumura D, Duda DG, Munn LL, Jain RK. Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation. 2010;17(3):206–225. https://doi.org/10.1111/j.1549-8719.2010.00029.x. PubMed PMID: 20374484; PubMed Central PMCID: PMCPMC2859831.CrossRef

Reeves KJ, Hurrell JE, Cecchini M, van der Pluijm G, Down JM, Eaton CL, et al. Prostate cancer cells home to bone using a novel in vivo model: modulation by the integrin antagonist GLPG0187. Int J Cancer 2015;136(7):1731–1740. https://doi.org/10.1002/ijc.29165. PubMed PMID: 25156971.CrossRef

Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 2010;24(18):1967–2000. https://doi.org/10.1101/gad.1965810. PubMed PMID: 20844012; PubMed Central PMCID: PMCPMC2939361.CrossRef

Hansen-Algenstaedt N, Schaefer C, Wolfram L, Joscheck C, Schroeder M, Algenstaedt P, et al. Femur window--a new approach to microcirculation of living bone in situ. J Orthop Res 2005;23(5):1073–1082. https://doi.org/10.1016/j.orthres.2005.02.013. PubMed PMID: 15890486.CrossRef

Lee IJ, Lee EJ, Park H, Kim W, Ha SJ, Shin YK, et al. Altered Biological Potential and Radioresponse of Murine Tumors in Different Microenvironments. Cancer Res Treat. 2016;48(2):727–737. https://doi.org/10.4143/crt.2014.350. PubMed PMID: 26323643; PubMed Central PMCID: PMCPMC4843754.CrossRef

Gu B, Espana L, Mendez O, Torregrosa A, Sierra A. Organ-selective chemoresistance in metastasis from human breast cancer cells: inhibition of apoptosis, genetic variability and microenvironment at the metastatic focus. Carcinogenesis 2004;25(12):2293–2301. https://doi.org/10.1093/carcin/bgh272. PubMed PMID: 15347599.CrossRef

10.

Monsky WL, Mouta Carreira C, Tsuzuki Y, Gohongi T, Fukumura D, Jain RK. Role of host microenvironment in angiogenesis and microvascular functions in human breast cancer xenografts: mammary fat pad versus cranial tumors. Clin Cancer Res 2002;8(4):1008–1013. PubMed PMID: 11948107.

11.

Jung YD, Ahmad SA, Akagi Y, Takahashi Y, Liu W, Reinmuth N, et al. Role of the tumor microenvironment in mediating response to anti-angiogenic therapy. Cancer Metastasis Rev 2000;19(1–2):147–157. PubMed PMID: 11191054.

12.

Gohongi T, Fukumura D, Boucher Y, Yun CO, Soff GA, Compton C, et al. Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1. Nat Med 1999;5(10):1203–1208. PubMed PMID: 10502827.CrossRef

13.

Yuan F, Salehi HA, Boucher Y, Vasthare US, Tuma RF, Jain RK. Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. Cancer Res. 1994;54(17):4564–8.PubMed

14.

Schaefer C, Fuhrhop I, Schroeder M, Viezens L, Otten J, Fiedler W, et al. Microcirculation of secondary bone tumors in vivo: the impact of minor surgery at a distal site. J Orthop Res 2010;28(11):1515–1521. https://doi.org/10.1002/jor.21166. PubMed PMID: 20872590.CrossRef

15.

Schaefer C, Schroeder M, Fuhrhop I, Viezens L, Otten J, Fiedler W, et al. Primary tumor dependent inhibition of tumor growth, angiogenesis, and perfusion of secondary breast cancer in bone. J Orthop Res 2011;29(8):1251–1258. https://doi.org/10.1002/jor.21402. PubMed PMID: 21381098.CrossRef

16.

Fuhrhop I, Schroeder M, Rafnsdottir SL, Viezens L, Ruther W, Hansen-Algenstaedt N, et al. Dynamics of microvascular remodelling during tumor growth in bone. J Orthop Res 2010;28(1):27–31. PubMed PMID: 19642113.

17.

Menger MD, Laschke MW, Vollmar B. Viewing the microcirculation through the window: some twenty years experience with the hamster dorsal skinfold chamber. Eur Surg Res. 2002;34(1–2):83–91. doi: 48893. PubMed PMID: 11867907.

18.

Yuan F, Leunig M, Berk DA, Jain RK. Microvascular permeability of albumin, vascular surface area, and vascular volume measured in human adenocarcinoma LS174T using dorsal chamber in SCID mice. Microvasc Res. 1993;45(3):269–89.CrossRef

19.

Hansen-Algenstaedt N, Joscheck C, Schaefer C, Lamszus K, Wolfram L, Biermann T, et al. Long-term observation reveals time-course-dependent characteristics of tumour vascularisation. Eur J Cancer 2005;41(7):1073–1085. https://doi.org/10.1016/j.ejca.2004.12.034. PubMed PMID: 15862758.CrossRef

20.

Brizel DM, Klitzman B, Cook JM, Edwards J, Rosner G, Dewhirst MW. A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model. Int J Radiat Oncol Biol Phys. 1993;25(2):269–76.CrossRef

21.

Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jain RK. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res 1994;54(13):3352–3356. PubMed PMID: 8012948.

22.

Simmons JK, Hildreth BE, 3rd, Supsavhad W, Elshafae SM, Hassan BB, Dirksen WP, et al. Animal Models of Bone Metastasis. Vet Pathol. 2015;52(5):827–841. https://doi.org/10.1177/0300985815586223. PubMed PMID: 26021553; PubMed Central PMCID: PMCPMC4545712.CrossRef

23.

Simpson-Abelson MR, Sonnenberg GF, Takita H, Yokota SJ, Conway TF, Jr., Kelleher RJ, Jr., et al. Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rgamma(null) mice. J Immunol 2008;180(10):7009–7018. PubMed PMID: 18453623.CrossRef

24.

Roth MD, Harui A. Human tumor infiltrating lymphocytes cooperatively regulate prostate tumor growth in a humanized mouse model. J Immunother Cancer. 2015;3:12. https://doi.org/10.1186/s40425-015-0056-2. PubMed PMID: 25901284; PubMed Central PMCID: PMCPMC4404579.

25.

Broderick L, Yokota SJ, Reineke J, Mathiowitz E, Stewart CC, Barcos M, et al. Human CD4+ effector memory T cells persisting in the microenvironment of lung cancer xenografts are activated by local delivery of IL-12 to proliferate, produce IFN-gamma, and eradicate tumor cells. J Immunol 2005;174(2):898–906. PubMed PMID: 15634912.CrossRef

26.

Ampuja M, Alarmo EL, Owens P, Havunen R, Gorska AE, Moses HL, et al. The impact of bone morphogenetic protein 4 (BMP4) on breast cancer metastasis in a mouse xenograft model. Cancer Lett 2016;375(2):238–244. https://doi.org/10.1016/j.canlet.2016.03.008. PubMed PMID: 26970275.CrossRef

27.

Pienta KJ, Abate-Shen C, Agus DB, Attar RM, Chung LW, Greenberg NM, et al. The current state of preclinical prostate cancer animal models. Prostate. 2008;68(6):629–639. https://doi.org/10.1002/pros.20726. PubMed PMID: 18213636; PubMed Central PMCID: PMCPMC3681409.CrossRef

28.

Kai L, Wang J, Ivanovic M, Chung YT, Laskin WB, Schulze-Hoepfner F, et al. Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1). Prostate 2011;71(3):268–280. https://doi.org/10.1002/pros.21240. PubMed PMID: 20717904.CrossRef

29.

Thibaudeau L, Taubenberger AV, Holzapfel BM, Quent VM, Fuehrmann T, Hesami P, et al. A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone. Dis Model Mech. 2014;7(2):299–309. https://doi.org/10.1242/dmm.014076. PubMed PMID: 24713276; PubMed Central PMCID: PMCPMC3917251.CrossRef

30.

Bauerle T, Komljenovic D, Berger MR, Semmler W. Multi-modal imaging of angiogenesis in a nude rat model of breast cancer bone metastasis using magnetic resonance imaging, volumetric computed tomography and ultrasound. J Vis Exp. 2012;(66):e4178. https://doi.org/10.3791/4178. PubMed PMID: 22929330; PubMed Central PMCID: PMCPMC3486767.

31.

Weissleder R. Scaling down imaging: molecular mapping of cancer in mice. Nat Rev Cancer 2002;2(1):11–18. https://doi.org/10.1038/nrc701. PubMed PMID: 11902581.CrossRef

32.

Fukumura D, Yuan F, Monsky WL, Chen Y, Jain RK. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am J Pathol 1997;151(3):679–688. PubMed PMID: 9284816.

33.

Sewell IA. Studies of the microcirculation using transparent tissue observation chambers inserted in the hamster cheek pouch. J Anat 1966;100(4):839–856. PubMed PMID: 5969981.

34.

Jain RK, Munn L, Fukumura D. Dissecting tumor pathophysiology using Intravital microscopy. Nature Review Cancer. 2002;2:266–76.CrossRef

35.

Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002;2(8):563–572. PubMed PMID: 12154349.CrossRef

36.

Wang Y, Revelo MP, Sudilovsky D, Cao M, Chen WG, Goetz L, et al. Development and characterization of efficient xenograft models for benign and malignant human prostate tissue. Prostate 2005;64(2):149–159. https://doi.org/10.1002/pros.20225. PubMed PMID: 15678503.CrossRef

37.

Price JE, Polyzos A, Zhang RD, Daniels LM. Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. Cancer Res 1990;50(3):717–721. PubMed PMID: 2297709.

38.

Buijs JT, van der Pluijm G. Osteotropic cancers: from primary tumor to bone. Cancer Lett 2009;273(2):177–193. https://doi.org/10.1016/j.canlet.2008.05.044. PubMed PMID: 18632203.CrossRef

39.

Holmgren L, O'Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995;1(2):149–153. PubMed PMID: 7585012.CrossRef

40.

Gimbrone MA, Jr., Cotran RS, Leapman SB, Folkman J. Tumor growth and neovascularization: an experimental model using the rabbit cornea. J Natl Cancer Inst 1974;52(2):413–427. PubMed PMID: 4816003.

41.

Agliano A, Martin-Padura I, Mancuso P, Marighetti P, Rabascio C, Pruneri G, et al. Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rgamma null mice generate a faster and more efficient disease compared to other NOD/scid-related strains. Int J Cancer 2008;123(9):2222–2227. https://doi.org/10.1002/ijc.23772. PubMed PMID: 18688847.CrossRef

42.

Pazzaglia UE, Congiu T, Raspanti M, Ranchetti F, Quacci D. Anatomy of the intracortical canal system: scanning electron microscopy study in rabbit femur. Clin Orthop Relat Res. 2009;467(9):2446–2456. https://doi.org/10.1007/s11999-009-0806-x. PubMed PMID: 19330389; PubMed Central PMCID: PMCPMC2866945.CrossRef

43.

Weiland AJ, Berggren A, Jones L. The acute effects of blocking medullary blood supply on regional cortical blood flow in canine ribs as measured by the hydrogen washout technique. Clin Orthop Relat Res 1982;(165):265–272. PubMed PMID: 7075070.

44.

Sottnik JL, Zhang J, Macoska JA, Keller ET. The PCa Tumor Microenvironment. Cancer Microenviron. 2011;4(3):283–297. https://doi.org/10.1007/s12307-011-0073-8. PubMed PMID: 21728070; PubMed Central PMCID: PMCPMC3234329.CrossRef

45.

Nemeth JA, Harb JF, Barroso U, Jr., He Z, Grignon DJ, Cher ML. Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone. Cancer Res 1999;59(8):1987–1993. PubMed PMID: 10213511.

46.

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285(21):1182–1186. PubMed PMID: 4938153.CrossRef

47.

Griffon-Etienne G, Boucher Y, Brekken C, Suit HD, Jain RK. Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications. Cancer Res 1999;59(15):3776–3782. PubMed PMID: 10446995.

48.

Schaefer C, Krause M, Fuhrhop I, Schroeder M, Algenstaedt P, Fiedler W, et al. Time-course-dependent microvascular alterations in a model of myeloid leukemia in vivo. Leukemia 2008;22(1):59–65. PubMed PMID: 17898789.CrossRef

49.

Patan S. Vasculogenesis and angiogenesis. Cancer Treat Res 2004;117:3–32. PubMed PMID: 15015550.

50.

Dvorak HF, Detmar M, Claffey KP, Nagy JA, van de Water L, Senger DR. Vascular permeability factor/vascular endothelial growth factor: an important mediator of angiogenesis in malignancy and inflammation. Int Arch Allergy Immunol 1995;107(1–3):233–235. PubMed PMID: 7542074.CrossRef

51.

Fidler IJ. Critical determinants of metastasis. Semin Cancer Biol 2002;12(2):89–96. https://doi.org/10.1006/scbi.2001.0416. PubMed PMID: 12027580.CrossRef

52.

Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, et al. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 2001;61(7):2929–2934. PubMed PMID: 11306470.

53.

Dvorak HF, Detmar M, Claffey KP, Nagy JA, van de Water L, Senger DR. Vascular permeability factor/vascular endothelial growth factor: an important mediator of angiogenesis in malignancy and inflammation. [review] [18 refs]. International Archives of Allergy & Immunology. 1995;107(1–3):233–5.CrossRef

54.

Chung LW, Baseman A, Assikis V, Zhau HE. Molecular insights into prostate cancer progression: the missing link of tumor microenvironment. J Urol 2005;173(1):10–20. https://doi.org/10.1097/01.ju.0000141582.15218.10. PubMed PMID: 15592017.CrossRef

55.

Hlatky L, Hahnfeldt P, Folkman J. Clinical application of antiangiogenic therapy: microvessel density, what it does and Doesn't tell us. JNCI Cancer Spectrum. 2002;94(12):883–93.

56.

Mussawy H, Viezens L, Hauenherm G, Schroeder M, Schaefer C. In vivo functional and morphological characterization of bone and striated muscle microcirculation in NSG mice. PLoS One 2017;12(8):e0183186. https://doi.org/10.1371/journal.pone.0183186. PubMed PMID: 28800593.CrossRef

57.

Virk MS, Alaee F, Petrigliano FA, Sugiyama O, Chatziioannou AF, Stout D, et al. Combined inhibition of the BMP pathway and the RANK-RANKL axis in a mixed lytic/blastic prostate cancer lesion. Bone. 2011;48(3):578–587. https://doi.org/10.1016/j.bone.2010.11.003. PubMed PMID: 21073986; PubMed Central PMCID: PMCPMC3039095.CrossRef

58.

Sottnik JL, Dai J, Zhang H, Campbell B, Keller ET. Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases. Cancer Res. 2015;75(11):2151–2158. https://doi.org/10.1158/0008-5472.CAN-14-2493. PubMed PMID: 25855383; PubMed Central PMCID: PMCPMC4452392.CrossRef

59.

Sottnik JL, Keller ET. Understanding and targeting osteoclastic activity in prostate cancer bone metastases. Curr Mol Med. 2013;13(4):626–639. PubMed PMID: 23061677; PubMed Central PMCID: PMCPMC3624036.CrossRef

Title: The bone microenvironment promotes tumor growth and tissue perfusion compared with striated muscle in a preclinical model of prostate cancer in vivo
Authors: Haider Mussawy
Lennart Viezens
Malte Schroeder
Svenja Hettenhausen
Jördis Sündermann
Jasmin Wellbrock
Kai Kossow
Christian Schaefer
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-018-4905-5

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