骨转移是肺癌常见的并发症之一。成骨性转移发生在肺癌骨转移中的机制仍不清楚,且70%的肺癌骨转移部位呈现溶骨性破坏,肺癌骨转移后显著增加的骨相关事件严重影响患者的生活质量。许多研究证实,肺癌细胞形态改变、骨微环境变化和免疫细胞与肺癌骨转移息息相关。本文作者从肺癌骨转移时肺癌细胞的上皮-间质转化、肺癌引起的骨微环境改变以及免疫细胞与肺癌骨转移的关系这3个方面,综述肺癌骨转移可能的机制。

[1] LEITER A,VELUSWAMY R R,WISNIVESKY J P.The global burden of lung cancer:current status and future trends[J].Nat Rev Clin Oncol,2023,20(9):624-639.
[2] YE W L,ZHAO Y P,CHENG Y,et al.Bone metastasis target redox-responsive micell for the treatment of lung cancerbone metastasis and anti-bone resorption[J].Artif Cells Nanomed Biotechnol,2018,46(sup1):380-391.
[3] WU S,PAN Y,MAO Y,et al.Current progress and mechanisms of bone metastasis in lung cancer:a narrative review[J].Transl Lung Cancer Res,2021,10(1):439-451.
[4] LAUFFENBURGER D A,HORWITZ A F.Cell migration:a physically integrated molecular process[J].Cell,1996,84(3):359-369.
[5] FRIEDL P,WOLF K.Tumour-cell invasion and migration:diversity and escape mechanisms[J].Nat Rev Cancer,2003,3(5):362-374.
[6] BURRIDGE K,CHRZANOWSKA-WODNICKA M.Focal adhesions,contractility,and signaling[J].Annu Rev Cell Dev Biol,1996,12:463-518.
[7] HU T,LU Y R.BCYRN1,a c-MYC-activated long non-coding RNA,regulates cell metastasis of non-small-cell lung cancer[J].Cancer Cell Int,2015,15:36.
[8] O'FLAHERTY J D,GRAY S,RICHARD D,et al.Circulating tumour cells,their role in metastasis and their clinical utility in lung cancer[J].Lung Cancer,2012,76(1):19-25.
[9] LUO Q,XU Z,WANG L,et al.Progress in the research on the mechanism of bone metastasis in lung cancer[J].Mol Clin Oncol,2016,5(2):227-235.
[10] ZHENG X Q,HUANG J F,LIN J L,et al.Incidence,prognostic factors,and a nomogram of lung cancer with bone metastasis at initial diagnosis:a population-based study[J].Transl Lung Cancer Res,2019,8(4):367-379.
[11] LAMOUILLE S,XU J,DERYNCK R.Molecular mechanisms of epithelial-mesenchymal transition[J].Nat Rev Mol Cell Biol,2014,15(3):178-196.
[12] NIETO M A,HUANG R Y,JACKSON R A,et al.EMT:2016[J].Cell,2016,166(1):21-45.
[13] XU M H,GAO X,LUO D,et al.EMT and acquisition of stem cell-like properties are involved in spontaneous formation of tumorigenic hybrids between lung cancer and bone marrow-derived mesenchymal stem cells[J].PLoS One,2014,9(2):e87893.
[14] CANO A,PEREZ-MORENO M A,RODRIGO I,et al.The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression[J].Nat Cell Biol,2000,2(2):76-83.
[15] HUANG Y,HONG W,WEI X.The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis[J].J Hematol Oncol,2022,15(1):129.
[16] HUBER M A,KRAUT N,BEUG H.Molecular requirements for epithelial-mesenchymal transition during tumor progression[J].Curr Opin Cell Biol,2005,17(5):548-558.
[17] APIEWSKA-PAJAKI P,KOWALSKA M A,BONCELA J.Expression and activity of SNAIL transcription factor during Epithelial to Mesenchymal Transition(EMT) in cancer progression[J].Postepy Hig Med Dosw(Online),2016,70:968-980.
[18] KAPLAN Z,ZIELSKE S P,IBRAHIM K G,et al.Wnt and beta-catenin signaling in the bone metastasis of prostate cancer[J].Life(Basel),2021,11(10):1009.
[19] TIRPE A A,GULEI D,CIORTEA S M,et al.Hypoxia:overview on hypoxia-mediated mechanisms with a focus on the role of HIF genes[J].Int J Mol Sci,2019,20(24):6140.
[20] KANG Y,CHEN C R,MASSAGUE J.A self-enabling TGF beta response coupled to stress signaling:Smad engages stress response factor ATF3 for Id1 repression in epithelial cells[J].Mol Cell,2003,11(4):915-926.
[21] CHEN X,WANG Z,DUAN N,et al.Osteoblast-osteoclast interactions[J].Connect Tissue Res,2018,59(2):99-107.
[22] KIKUTA J,ISHII M.Bone imaging:osteoclast and osteoblast dynamics[J].Methods Mol Biol,2018,1763:1-9.
[23] XU S,YANG F,LIU R,et al.Serum microRNA-139-5p is downregulated in lung cancer patients with lytic bone metastasis[J].Oncol Rep,2018,39(5):2376-2384.
[24] KANE J F,JOHNSON R W.Re-evaluating the role of PTHrP in breast cancer[J].Cancers(Basel),2023,15(10):2670.
[25] WEILBAECHER K N,GUISE T A,MCCAULEY L K.Cancer to bone:a fatal attraction[J].Nat Rev Cancer,2011,11(6):411-425.
[26] CHIANG A C,MASSAGUE J.Molecular basis of metastasis[J].N Engl J Med,2008,359(26):2814-2823.
[27] SUVA L J,WASHAM C,NICHOLAS R W,et al.Bone metastasis:mechanisms and therapeutic opportunities[J].Nat Rev Endocrinol,2011,7(4):208-218.
[28] OTLEY M O C,SINAL C J.Adipocyte-cancer cell interactions in the bone microenvironment[J].Front Endocrinol(Lausanne),2022,13:903925.
[29] LUO G,TANG M,ZHAO Q,et al.Bone marrow adipocytes enhance osteolytic bone destruction by activating 1q21.3(S100A7/8/9-IL6R)-TLR4 pathway in lung cancer[J].J Cancer Res Clin Oncol,2020,146(9):2241-2253.
[30] AZIZIDOOST S,BABASHAH S,RAHIM F,et al.Bone marrow neoplastic niche in leukemia[J].Hematology,2014,19(4):232-238.
[31] CALVI L M,ADAMS G B,WEIBRECHT K W,et al.Osteoblastic cells regulate the haematopoietic stem cell niche[J].Nature,2003,425(6960):841-846.
[32] PARK S I,LEE C,SADLER W D,et al.Parathyroid hormone-related protein drives a CD11b⁺Gr1⁺cell-mediated positivefeedback loop to support prostate cancer growth[J].Cancer Res,2013,73(22):6574-6583.
[33] SHIOZAWA Y,PEDERSEN E A,HAVENS A M,et al.Human prostate cancer metastases target the hematopoietic stem cell niche toestablish footholds in mouse bone marrow[J].J Clin Invest,2011,121(4):1298-1312.
[34] SHIOZAWA Y,PIENTA K J,TAICHMAN R S.Hematopoietic stem cell niche is a potential therapeutic target for bonemetastatic tumors[J].Clin Cancer Res,2011,17(17):5553-5558.
[35] SHI Y,RIESE D J N D,SHEN J.The role of the CXCL12/CXCR4/CXCR7 chemokine axis in cancer[J].Front Pharmacol,2020,11:574667.
[36] AGUILA H L,ROWE D W.Skeletal development,bone remodeling,and hematopoiesis[J].Immunol Rev,2005,208:7-18.
[37] KOSTENUIK P J,SHALHOUB V.Osteoprotegerin:a physiological and pharmacological inhibitor of bone resorption[J].Curr Pharm Des,2001,7(8):613-635.
[38] WONG B R,JOSIEN R,LEE S Y,et al.TRANCE(tumor necrosis factor [TNF]-related activation-induced cytokine),a new TNF family member predominantly expressed in T cells,is a dendritic cell-specific survival factor[J].J Exp Med,1997,186(12):2075-2080.
[39] DUAN M C,ZHONG X N,LIU G N,et al.The Treg/Th17 paradigm in lung cancer[J].J Immunol Res,2014,2014:730380.
[40] BARUA S,FANG P,SHARMA A,et al.Spatial interaction of tumor cells and regulatory T cells correlates with survival in non-small cell lung cancer[J].Lung Cancer,2018,117:73-79.
[41] BUDNA J,SPYCHALSKI L,KACZMAREK M,et al.Regulatory T cells in malignant pleural effusions subsequent to lung carcinoma and their impact on the course of the disease[J].Immunobiology,2017,222(3):499-505.
[42] CHEN Y Q,SHI H Z,QIN X J,et al.CD4⁺CD25⁺ regulatory T lymphocytes in malignant pleural effusion[J].Am J Respir Crit Care Med,2005,172(11):1434-1439.
[43] SMYTH M J,TENG M W,SWANN J,et al.CD4⁺CD25⁺ T regulatory cells suppress NK cell-mediated immunotherapy of cancer[J].J Immunol,2006,176(3):1582-1587.
[44] ZHAO E,WANG L,DAI J,et al.Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer[J].Oncoimmunology,2012,1(2):152-161.
[45] MANOLAGAS S C.Birth and death of bone cells:basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis[J].Endocr Rev,2000,21(2):115-137.
[46] PRITCHARD A,TOUSIF S,WANG Y,et al.Lung tumor cell-derived exosomes promote M2 macrophage polarization[J].Cells,2020,9(5):1303.
[47] RAO X,ZHOU X,WANG G,et al.NLRP6 is required for cancer-derived exosome-modified macrophage M2 polarization and promotes metastasis in small cell lung cancer[J].Cell Death Dis,2022,13(10):891.
[48] BORDUKALO-NIKSIC T,KUFNER V,VUKICEVIC S.The role of BMPs in the regulation of osteoclasts resorption and bone remodeling:from experimental models to clinical applications[J].Front Immunol,2022,13:869422.
[49] HUANG F,CAO Y,WU G,et al.BMP2 signalling activation enhances bone metastases of non-small cell lung cancer[J].J Cell Mol Med,2020,24(18):10768-10784.
[50] GONDA K,SHIBATA M,OHTAKE T,et al.Myeloid-derived suppressor cells are increased and correlated with type 2 immune responses,malnutrition,inflammation,and poor prognosis in patients with breast cancer[J].Oncol Lett,2017,14(2):1766-1774.
[51] IDORN M,KOLLGAARD T,KONGSTED P,et al.Correlation between frequencies of blood monocytic myeloid-derived suppressor cells,regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer[J].Cancer Immunol Immunother,2014,63(11):1177-1187.
[52] HUANG B,LEI Z,ZHAO J,et al.CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers[J].Cancer Lett,2007,252(1):86-92.
[53] DANILIN S,MERKEL A R,JOHNSON J R,et al.Myeloid-derived suppressor cells expand during breast cancer progression and promote tumor-induced bone destruction[J].Oncoimmunology,2012,1(9):1484-1494.
[54] ORTIZ M L,LU L,RAMACHANDRAN I,et al.Myeloid-derived suppressor cells in the development of lung cancer[J].Cancer Immunol Res,2014,2(1):50-58.
[55] ARELLANO D L,JUAREZ P,VERDUGO-MEZA A,et al.Bone microenvironment-suppressed T cells increase osteoclast formation and osteolytic bone metastases in mice[J].J Bone Miner Res,2022,37(8):1446-1463.
[56] LAURET M J E,LAHEURTE C,JARY M,et al.Immunoregulation and clinical implications of ANGPT₂/TIE⁺₂ M-MDSC signature in non-small cell lung cancer[J].Cancer Immunol Res,2020,8(2):268-279.