摘要
Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(CSCs) are positively correlated with VM. In this study, triple-negative breast cancer(TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs.Methods: The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples.The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs.Results: CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro. MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo.Conclusions: CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC.
Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(CSCs) are positively correlated with VM. In this study, triple-negative breast cancer(TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs.Methods: The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples.The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs.Results: CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro. MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo.Conclusions: CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC.
引文
1. Watnick RS,Cheng YN,Rangarajan A,Ince TA,Weinberg RA.Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis.Cancer Cell.2003;3:219-31.
2. Sun BC,Zhang DF,Zhao N,Zhao XL.Epithelial-to-endothelial transition and cancer stem cells:two cornerstones of vasculogenic mimicry in malignant tumors.Oncotarget.2017;8:30502-10.
3. Jones EA,le Noble F,Eichmann A.What determines blood vessel structure?Genetic prespecification vs.Hemodynamics Physiology(Bethesda).2006;21:388-95.
4. Seftor RE,Hess AR,Seftor EA,Kirschmann DA,Hardy KM,Margaryan NV,et al.Tumor cell vasculogenic mimicry:from controversy to therapeutic promise.Am J Pathol.2012;181:1115-25.
5. Seftor EA,Seftor REB,Weldon DS,Kirsammer GT,Margaryan NV Gilgur A,et al.Melanoma tumor cell heterogeneity:a molecular approach to study subpopulations expressing the embryonic morphogen nodal.Semin Oncol.2014;41:259-66.
6. Yao LL,Zhang DF,Zhao XL,Sun BC,Liu YR,Gu Q,et al.Dickkopf-1-promoted vasculogenic mimicry in non-small cell lung cancer is associated with EMT and development of a cancer stemlike cell phenotype.J Cell Mol Med.2016;20:1673-85.
7. Sun T,Sun BC,Zhao XL,Zhao N,Dong XY,Che N,et al.Promotion of tumor cell metastasis and vasculogenic mimicry by way of transcription coactivation by Bcl-2 and Twist1:a study of hepatocellular carcinoma.Hepatology.2011;54:1690-706.
8. Du J,Sun BC,Zhao XL,Gu Q,Dong XY,Mo J,et al.Hypoxia promotes vasculogenic mimicry formation by inducing epithelialmesenchymal transition in ovarian carcinoma.Gynecol Oncol.2014;133:575-83.
9. Zhang L,Xu YY,Sun JT,Chen WL,Zhao L,Ma C,et al.M2-like tumor-associated macrophages drive vasculogenic mimicry through amplification of IL-6 expression in glioma cells.Oncotarget.2017;8:819-32.
10. Zhang DF,Sun BC,Zhao XL,Ma YM,Ji R,Gu Q,et al.Twistl expression induced by sunitinib accelerates tumor cell vasculogeni 11. Sasanelli F,Hocking A,Pulford E,Irani Y,Klebe S.Vasculogenic mimicry in vitro in tumour cells derived from metastatic malignant pleural effusions.Pathology.2017;49:537-39.
12. Dunleavey JM,Dudley AC.Vascular mimicry:concepts and implications for anti-angiogenic therapy.Curr Angiogenes.2012;1:133-8.
13. Seftor EA,Meltzer PS,Schatteman GC,Gruman LM,Hess AR,Kirschmann DA,et al.Expression of multiple molecular phenotypes by aggressive melanoma tumor cells:role in vasculogenic mimicry.Crit Rev Oncol Hematol.2002;44:17-27.
14. Gu JW,Rizzo P,Pannuti A,Golde T,Osborne B,Miele L.Notch signals in the endothelium and cancer"Stem-like"Cells:opportunities for cancer therapy.Vasc Cell.2012;4:7.
15. Wang Y,Sun HZ,Zhang DF,Fan D,Zhang YI-H,Dong XY,et al.TP53INP1 inhibits hypoxia-induced vasculogenic mimicry formation via the ROS/snail signalling axis in breast cancer.J Cell Mol Med.2018;22:3475-88.
16. Lehmann BD,Bauer JA,Chen X,Sanders ME,Chakravarthy AB,Shyr Y,et al.Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.J Clin Invest.2011;121:2750-67.
17. de Azambuja E,Cardoso F,Meirsman L,Straehle C,Dolci S,Vantongelen K,et al.The new generation of breast cancer clinical trials:the right drug for the right target.Bull Cancer.2008;95:352-7.
18. Kirschmann DA,Seftor EA,Hardy KM,Seftor REB,Hendrix MJC.Molecular pathways:vasculogenic mimicry in tumor cells:diagnostic and therapeutic implications.Clin Cancer Res.2012;18:2726-32.
19. Kurzrock R,Stewart DJ.Exploring the benefit/risk associated with antiangiogenic agents for the treatment of non-small cell lung cancer patients.Clin Cancer Res.2017;23:1137-48.
20. Hendrix MJC,Seftor EA,Hess AR,Seftor REB.Vasculogenic mimicry and tumour-cell plasticity:lessons from melanoma.Nat Rev Cancer.2003;3:411-21.
21. Maniotis AJ,Folberg R,Hess A,Seftor EA,Gardner LMG,Pe,er J,et al.Vascular channel formation by human melanoma cells in vivo and in vitro:vasculogenic mimicry.Am J Pathol.1999;155:739-52.
22. Hendrix MJC,Seftor EA,Hess AR,Seftor REB.Molecular plasticity of human melanoma cells.Oncogene.2003;22:3070-5.
23. Mei X,Chen YS,Chen FR,Xi SY,Chen ZP.Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging.Neuro Oncol.2017;19:1109-18.
24. Folberg R,Arbieva Z,Moses J,Hayee A,Sandal T,Kadkol S,et al.Tumor cell plasticity in uveal melanoma:microenvironment directed dampening of the invasive and metastatic genotype and phenotype accompanies the generation of vasculogenic mimicry patterns.Am J Pathol.2006;169:1376-89.
25. Huang MG,Liu TR,Ma PH,Mitteer RA Jr,Zhang ZT,Kim HJ,et al.c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma.J Clin Invest.2016;126:1801-14.
26. Zhang YH,Sun BC,Zhao XL,Liu ZY,Wang XD,Yao X,et al.Clinical significances and prognostic value of cancer stem-like cells markers and vasculogenic mimicry in renal cell carcinoma.J Surg Oncol.2013; 108:414-9.
27. Zhao XL,Sun BC,Sun D,Liu TJ,Che N,Gu Q,et al.Slug promotes hepatocellular cancer cell progression by increasing sox2 and nanog expression.Oncol Rep.2015;33:149-56.
28. Francescone R,Scully S,Bentley B,Yan W,Taylor SL,Oh D,et al.Glioblastoma-derived tumor cells induce vasculogenic mimicry through Flk-1 protein activation.J Biol Chem.2012;287:24821-31.
29. Comanescu M,Bussolati G.Cancer stem cells biomarkers in triple negative invasive carcinoma of the breast and associated in situ lesions.Rom J Morphol Embryol.2014;55:569-74.
30. Curtis C,Shah SP,Chin SF,Turashvili G,Rueda OM,Dunning MJ,et al.The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.Nature.2012;486:346-52.
31. Tsukabe M,Shimazu K,Morimoto K,Naoi Y,Kagara N,Shimoda M,et al.Clinicopathological analysis of breast ductal carcinoma in situ with ALDH1-positive cancer stem cells.Oncology.2013;85:248-56.
32. Idowu MO,Kmieciak M,Dumur C,Burton RS,Grimes MM,Powers CN,et al.CD44+/CD24-/low cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome.Hum Pathol.2012;43:364-73.
33. Chiche A,Moumen M,Romagnoli M,Petit V,Lasla H,Jezequel P,et al.p53 deficiency induces cancer stem cell pool expansion in a mouse model of triple-negative breast tumors.Oncogene.2017;36:2355-65.
34. Pohl SG,Brook N,Agostino M,Arfuso F,Kumar AP,Dharmarajan A.Wnt signaling in triple-negative breast cancer.Oncogenesis.2017;6:e310.
35. Prieto-Vila M,Yan T,Calle AS,Nair N,Hurley L,Kasai T,et al.iPSC-derived cancer stem cells provide a model of tumor vasculature.Am J Cancer Res.2016;6:1906-21.
36. Nwabo Kamdje AH,Kamga PT,Simo RT,Vecchio L,Seke Etet PF,Muller JM,et al.Mesenchymal stromal cells'role in tumor microenvironment:involvement of signaling pathways.Cancer Biol Med.2017;14:129-141.
37. Wang R,Chadalavada K,Wilshire J,Kowalik U,Hovinga KE,Geber A,et al.Glioblastoma stem-like cells give rise to tumour endothelium.Nature.2010;468:829-33.
38. Ricci-Vitiani L,Pallini R,Biffoni M,Todaro M,Invernici G,Cenci T,et al.Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells.Nature.2010;468:824-8.
39. Guelfi S,Duffau H,Bauchet L,Rothhut B,Hugnot JP.Vascular transdifferentiation in the CNS:a focus on neural and glioblastoma stem-like cells.Stem Cells Int.2016;2016:2759403.
40. Bussolati B,Grange C,Sapino A,Camussi G.Endothelial cell differentiation of human breast tumour stem/progenitor cells.J Cell Mol Med.2009;13:309-19.
41. Shima H,Yamada A,Ishikawa T,Endo I.Are breast cancer stem cells the key to resolving clinical issues in breast cancer therapy?Gland Surg.2017;6:82-8.
42. Zhang CZ,Samanta D,Lu HQ,Bullen JW,Zhang HM,Chen I,et al.Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA.Proc Natl Acad Sci USA.2016;113:E2047-56.
43. Conley SJ,Gheordunescu E,Kakarala P,Newman B,Korkaya H,Heath AN,et al.Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia.Proc Natl Acad Sci USA.2012;109:2784-9.
44. Wang H,Huang B,Li BM,Cao KY,Mo CQ,Jiang SJ,et al.ZEB1-mediated vasculogenic mimicry formation associates with epithelial-mesenchymal transition and cancer stem cell phenotypes in prostate cancer.J Cell Mol Med.2018;22:3768-81.
45. Rothhammer T,Bataille F,Spruss T,Eissner G,Bosserhoff AK.Functional implication of BMP4 expression on angiogenesis in malignant melanoma.Oncogene.2007;26:4158-70.
46. Sun JY,Sun BC,Sun R,Zhu DW,Zhao XL,Zhang YH,et al.HMGA2 promotes vasculogenic mimicry and tumor aggressiveness by upregulating twistl in gastric carcinoma.Sci Rep.2017;7:2229.
47. Samanta S,Sun H,Goel HL,Pursell B,Chang C,Khan A,et al.IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG.Oncogene.2016;35:1111-21.
48. Nwabo Kamdje AH,Takam Kamga P,Tagne Simo R,Vecchio L,Seke Etet PF,Muller JM,et al.Developmental pathways associated with cancer metastasis:notch,Wnt,and hedgehog.Cancer Biol Med.2017;14:109-20.
49. Hardy KM,Kirschmann DA,Seftor EA,Margaryan NV,Postovit LM,Strizzi L,et al.Regulation of the embryonic morphogen Nodal by Notch4 facilitates manifestation of the aggressive melanoma phenotype.Cancer Res.2010;70:10340-50.
50. Piha-Paul SA,Munster PN,Hollebecque A,Argiles G,Dajani O,Cheng JD,et al.Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours.Eur J Cancer.2015;51:1865-73.
51. Nagamatsu I,Onishi H,Matsushita S,Kubo M,Kai M,Imaizumi A,et al.NOTCH4 is a potential therapeutic target for triplenegative breast cancer.Anticancer Res.2014;34:69-80.
