Endocrinol Metab.  2016 Dec;31(4):485-492. 10.3803/EnM.2016.31.4.485.

Osteoblasts Are the Centerpiece of the Metastatic Bone Microenvironment

• Jeong HM
• Cho SW
• Park SI

• KMID: 2373065
• DOI: http://doi.org/10.3803/EnM.2016.31.4.485

Abstract

The tumor microenvironment is comprised of diverse stromal cell populations in addition to tumor cells. Increasing evidence now clearly supports the role of microenvironment stromal cells in tumor progression and metastasis, yet the regulatory mechanisms and interactions among tumor and stromal cells remain to be elucidated. Bone metastasis is the major problem in many types of human malignancies including prostate, breast and lung cancers, and the biological basis of bone metastasis let alone curative approaches are largely undetermined. Among the many types of stromal cells in bone, osteoblasts are shown to be an important player. In this regard, osteoblasts are a key target cell type in the development of bone metastasis, but there are currently no drugs or therapeutic approaches are available that specifically target osteoblasts. This review paper summarizes the current knowledge on osteoblasts in the metastatic tumor microenvironment, aiming to provide clues and directions for future research endeavor.

Keyword

Neoplasms; Neoplasm metastasis; Bone and bones; Microenvironment; Osteoblasts; Osteoclasts

MeSH Terms

Bone and Bones
Breast
Humans
Linear Energy Transfer
Lung Neoplasms
Neoplasm Metastasis
Osteoblasts*
Osteoclasts
Prostate
Stromal Cells
Tumor Microenvironment

Figure

• 

  Fig. 1 PC-3, metastatic human prostate cancer cells, were injected in to the proximal tibia of male athymic nude mice [57]. Tumors (Tu) were harvested after 3 weeks, followed by fixation, decalcification, sectioning, and modified H&E staining (showing bone matrices in orange) [58]. Osteoblasts (Obl), physiologically unilayer cells, formed multiple layers (indicating proliferation; bracket), with woven bone (WB; newly formed bone; solid arrow) formation around the tumor tissue (dotted line). Lamellar bone (LB; remodeled bone) and osteoclasts (Ocl) are clearly visible. This data supports that osteoblasts are actively respond to metastatic tumor cells, and potentially play important roles in bone metastasis. BM, bone marrow.

Reference

1. Buenrostro D, Park SI, Sterling JA. Dissecting the role of bone marrow stromal cells on bone metastases. Biomed Res Int. 2014; 2014:875305. PMID: 25054153.

2. Soki FN, Park SI, McCauley LK. The multifaceted actions of PTHrP in skeletal metastasis. Future Oncol. 2012; 8:803–817. PMID: 22830401.

3. Park SI, Soki FN, McCauley LK. Roles of bone marrow cells in skeletal metastases: no longer bystanders. Cancer Microenviron. 2011; 4:237–246. PMID: 21809058.

4. Schneider A, Kalikin LM, Mattos AC, Keller ET, Allen MJ, Pienta KJ, et al. Bone turnover mediates preferential localization of prostate cancer in the skeleton. Endocrinology. 2005; 146:1727–1736. PMID: 15637291.

5. Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, et al. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell. 2013; 154:1060–1073. PMID: 23993096.

6. Park SI, Lee C, Sadler WD, Koh AJ, Jones J, Seo JW, et al. Parathyroid hormone-related protein drives a CD11b+Gr1+ cell-mediated positive feedback loop to support prostate cancer growth. Cancer Res. 2013; 73:6574–6583. PMID: 24072746.

7. Ding X, Park SI, McCauley LK, Wang CY. Signaling between transforming growth factor β (TGF-β) and transcription factor SNAI2 represses expression of microRNA miR-203 to promote epithelial-mesenchymal transition and tumor metastasis. J Biol Chem. 2013; 288:10241–10253. PMID: 23447531.

8. Rattanakul C, Lenbury Y, Krishnamara N, Wollkind DJ. Modeling of bone formation and resorption mediated by parathyroid hormone: response to estrogen/PTH therapy. Biosystems. 2003; 70:55–72. PMID: 12753937.

9. Kang Y. Dissecting tumor-stromal interactions in breast cancer bone metastasis. Endocrinol Metab (Seoul). 2016; 31:206–212. PMID: 27184014.

10. Lee YJ, Park CH, Lee YK, Ha YC, Koo KH. Which bisphosphonate? It's the compliance!: decision analysis. J Bone Metab. 2016; 23:79–83. PMID: 27294079.

11. Kim W, Chung Y, Kim SH, Park S, Bae JH, Kim G, et al. Increased sclerostin levels after further ablation of remnant estrogen by aromatase inhibitors. Endocrinol Metab (Seoul). 2015; 30:58–64. PMID: 25827459.

12. Lee Y, Schwarz E, Davies M, Jo M, Gates J, Wu J, et al. Differences in the cytokine profiles associated with prostate cancer cell induced osteoblastic and osteolytic lesions in bone. J Orthop Res. 2003; 21:62–72. PMID: 12507581.

13. Shimo T, Matsumoto K, Takabatake K, Aoyama E, Takebe Y, Ibaragi S, et al. The role of sonic hedgehog signaling in osteoclastogenesis and jaw bone destruction. PLoS One. 2016; 11:e0151731. PMID: 27007126.

14. Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006; 440:692–696. PMID: 16572175.

15. Huang H, Chang EJ, Ryu J, Lee ZH, Lee Y, Kim HH. Induction of c-Fos and NFATc1 during RANKL-stimulated osteoclast differentiation is mediated by the p38 signaling pathway. Biochem Biophys Res Commun. 2006; 351:99–105. PMID: 17052691.

16. Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 2004; 15:457–475. PMID: 15561602.

17. Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002; 3:889–901. PMID: 12479813.

18. Chan LH, Wang W, Yeung W, Deng Y, Yuan P, Mak KK. Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression. Oncogene. 2014; 33:4857–4866. PMID: 24141783.

19. Cannonier SA, Sterling JA. The role of hedgehog signaling in tumor induced bone disease. Cancers (Basel). 2015; 7:1658–1683. PMID: 26343726.

20. Sterling JA, Oyajobi BO, Grubbs B, Padalecki SS, Munoz SA, Gupta A, et al. The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells. Cancer Res. 2006; 66:7548–7553. PMID: 16885353.

21. Johnson RW, Nguyen MP, Padalecki SS, Grubbs BG, Merkel AR, Oyajobi BO, et al. TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res. 2011; 71:822–831. PMID: 21189326.

22. Alexaki VI, Javelaud D, Van Kempen LC, Mohammad KS, Dennler S, Luciani F, et al. GLI2-mediated melanoma invasion and metastasis. J Natl Cancer Inst. 2010; 102:1148–1159. PMID: 20660365.

23. Das S, Samant RS, Shevde LA. The hedgehog pathway conditions the bone microenvironment for osteolytic metastasis of breast cancer. Int J Breast Cancer. 2012; 2012:298623. PMID: 22295244.

24. Zhang X, Akech J, Browne G, Russell S, Wixted JJ, Stein JL, et al. Runx2-Smad signaling impacts the progression of tumor-induced bone disease. Int J Cancer. 2015; 136:1321–1332. PMID: 25053011.

25. Stein GS, Lian JB, van Wijnen AJ, Stein JL, Montecino M, Javed A, et al. Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression. Oncogene. 2004; 23:4315–4329. PMID: 15156188.

26. Wang DC, Wang HF, Yuan ZN. Runx2 induces bone osteolysis by transcriptional suppression of TSSC1. Biochem Biophys Res Commun. 2013; 438:635–639. PMID: 23933319.

27. Baniwal SK, Khalid O, Gabet Y, Shah RR, Purcell DJ, Mav D, et al. Runx2 transcriptome of prostate cancer cells: insights into invasiveness and bone metastasis. Mol Cancer. 2010; 9:258. PMID: 20863401.

28. Franceschi RT, Xiao G. Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. J Cell Biochem. 2003; 88:446–454. PMID: 12532321.

29. Xiao G, Jiang D, Gopalakrishnan R, Franceschi RT. Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. J Biol Chem. 2002; 277:36181–36187. PMID: 12110689.

30. Yang S, Wei D, Wang D, Phimphilai M, Krebsbach PH, Franceschi RT. In vitro and in vivo synergistic interactions between the Runx2/Cbfa1 transcription factor and bone morphogenetic protein-2 in stimulating osteoblast differentiation. J Bone Miner Res. 2003; 18:705–715. PMID: 12674331.

31. Franceschi RT, Xiao G, Jiang D, Gopalakrishnan R, Yang S, Reith E. Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation. Connect Tissue Res. 2003; 44(Suppl 1):109–116.

32. Jiang D, Franceschi RT, Boules H, Xiao G. Parathyroid hormone induction of the osteocalcin gene. Requirement for an osteoblast-specific element 1 sequence in the promoter and involvement of multiple-signaling pathways. J Biol Chem. 2004; 279:5329–5337. PMID: 14634012.

33. Zong JC, Wang X, Zhou X, Wang C, Chen L, Yin LJ, et al. Gut-derived serotonin induced by depression promotes breast cancer bone metastasis through the RUNX2/PTHrP/RANKL pathway in mice. Oncol Rep. 2016; 35:739–748. PMID: 26573960.

34. Li XQ, Du X, Li DM, Kong PZ, Sun Y, Liu PF, et al. ITGBL1 is a Runx2 transcriptional target and promotes breast cancer bone metastasis by activating the TGFβ signaling pathway. Cancer Res. 2015; 75:3302–3313. PMID: 26060017.

35. Li XQ, Lu JT, Tan CC, Wang QS, Feng YM. RUNX2 promotes breast cancer bone metastasis by increasing integrin α5-mediated colonization. Cancer Lett. 2016; 380:78–86. PMID: 27317874.

36. Ge C, Zhao G, Li Y, Li H, Zhao X, Pannone G, et al. Role of Runx2 phosphorylation in prostate cancer and association with metastatic disease. Oncogene. 2016; 35:366–376. PMID: 25867060.

37. Dai J, Keller J, Zhang J, Lu Y, Yao Z, Keller ET. Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Res. 2005; 65:8274–8285. PMID: 16166304.

38. Feeley BT, Gamradt SC, Hsu WK, Liu N, Krenek L, Robbins P, et al. Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer. J Bone Miner Res. 2005; 20:2189–2199. PMID: 16294272.

39. Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, et al. Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene. 2010; 29:811–821. PMID: 19915614.

40. Park SI, Shah AN, Zhang J, Gallick GE. Regulation of angiogenesis and vascular permeability by Src family kinases: opportunities for therapeutic treatment of solid tumors. Expert Opin Ther Targets. 2007; 11:1207–1217. PMID: 17845146.

41. Park SI, McCauley LK. Nuclear localization of parathyroid hormone-related peptide confers resistance to anoikis in prostate cancer cells. Endocr Relat Cancer. 2012; 19:243–254. PMID: 22291434.

42. Maruyama Z, Yoshida CA, Furuichi T, Amizuka N, Ito M, Fukuyama R, et al. Runx2 determines bone maturity and turnover rate in postnatal bone development and is involved in bone loss in estrogen deficiency. Dev Dyn. 2007; 236:1876–1890. PMID: 17497678.

43. Khalid O, Baniwal SK, Purcell DJ, Leclerc N, Gabet Y, Stallcup MR, et al. Modulation of Runx2 activity by estrogen receptor-alpha: implications for osteoporosis and breast cancer. Endocrinology. 2008; 149:5984–5995. PMID: 18755791.

44. van der Deen M, Akech J, Wang T, FitzGerald TJ, Altieri DC, Languino LR, et al. The cancer-related Runx2 protein enhances cell growth and responses to androgen and TGFbeta in prostate cancer cells. J Cell Biochem. 2010; 109:828–837. PMID: 20082326.

45. Hutvagner G, Zamore PD. A microRNA in a multiple-turnover RNAi enzyme complex. Science. 2002; 297:2056–2060. PMID: 12154197.

46. Zeng Y, Yi R, Cullen BR. MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci U S A. 2003; 100:9779–9784. PMID: 12902540.

47. Saini S, Majid S, Yamamura S, Tabatabai L, Suh SO, Shahryari V, et al. Regulatory role of mir-203 in prostate cancer progression and metastasis. Clin Cancer Res. 2011; 17:5287–5298. PMID: 21159887.

48. Ell B, Mercatali L, Ibrahim T, Campbell N, Schwarzenbach H, Pantel K, et al. Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell. 2013; 24:542–556. PMID: 24135284.

49. Martello G, Rosato A, Ferrari F, Manfrin A, Cordenonsi M, Dupont S, et al. A microRNA targeting dicer for metastasis control. Cell. 2010; 141:1195–1207. PMID: 20603000.

50. Gururajan M, Josson S, Chu GC, Lu CL, Lu YT, Haga CL, et al. miR-154^* and miR-379 in the DLK1-DIO3 microRNA mega-cluster regulate epithelial to mesenchymal transition and bone metastasis of prostate cancer. Clin Cancer Res. 2014; 20:6559–6569. PMID: 25324143.

51. Josson S, Gururajan M, Hu P, Shao C, Chu GY, Zhau HE, et al. miR-409-3p/-5p promotes tumorigenesis, epithelial-to-mesenchymal transition, and bone metastasis of human prostate cancer. Clin Cancer Res. 2014; 20:4636–4646. PMID: 24963047.

52. Morgani SM, Canham MA, Nichols J, Sharov AA, Migueles RP, Ko MS, et al. Totipotent embryonic stem cells arise in ground-state culture conditions. Cell Rep. 2013; 3:1945–1957. PMID: 23746443.

53. Josson S, Gururajan M, Sung SY, Hu P, Shao C, Zhau HE, et al. Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis. Oncogene. 2015; 34:2690–2699. PMID: 25065597.

54. Li X, Koh AJ, Wang Z, Soki FN, Park SI, Pienta KJ, et al. Inhibitory effects of megakaryocytic cells in prostate cancer skeletal metastasis. J Bone Miner Res. 2011; 26:125–134. PMID: 20684002.

55. Jung Y, Shiozawa Y, Wang J, McGregor N, Dai J, Park SI, et al. Prevalence of prostate cancer metastases after intravenous inoculation provides clues into the molecular basis of dormancy in the bone marrow microenvironment. Neoplasia. 2012; 14:429–439. PMID: 22745589.

56. Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011; 121:1298–1312. PMID: 21436587.

57. Park SI, Kim SJ, McCauley LK, Gallick GE. Pre-clinical mouse models of human prostate cancer and their utility in drug discovery. Curr Protoc Pharmacol. 2010; Chapter 14:Unit 14.15.

58. Campbell JP, Karolak MR, Ma Y, Perrien DS, Masood-Campbell SK, Penner NL, et al. Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. PLoS Biol. 2012; 10:e1001363. PMID: 22815651.