Skip to main content

Advertisement

SpringerLink
Log in

Luminal breast cancer metastasis is dependent on estrogen signaling

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Luminal breast cancer is the most frequently encountered type of human breast cancer and accounts for half of all breast cancer deaths due to metastatic disease. We have developed new in vivo models of disseminated human luminal breast cancer that closely mimic the human disease. From initial lesions in the tibia, locoregional metastases develop predictably along the iliac and retroperitoneal lymph node chains. Tumors cells retain their epithelioid phenotype throughout the process of dissemination. In addition, systemically injected metastatic MCF-7 cells consistently give rise to metastases in the skeleton, floor of mouth, adrenal glands, as well as in the lungs, liver, brain and mammary fat pad. We show that growth of luminal breast cancer metastases is highly dependent on estrogen in a dose-dependent manner and that estrogen withdrawal induces rapid growth arrest of metastatic disease. On the other hand, even though micrometastases at secondary sites remain viable in the absence of estrogen, they are dormant and do not progress to macrometastases. Thus, homing to and seeding of secondary sites do not require estrogen. Moreover, in sharp contrast to basal-like breast cancer metastasis in which transforming growth factor-β signaling plays a key role, luminal breast cancer metastasis is independent of this cytokine. These findings have important implications for the development of targeted anti-metastatic therapy for luminal breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

EMT:

Epithelial-to-mesenchymal transitions

TGF-β:

Transforming growth factor-β

ERα:

Estrogen receptor α

TGFBR2 :

TGF-β type II receptor gene

Ara-C:

Cytosine-β-d-arabinofuranoside-hydrochloride

ESR1 :

Estrogen receptor α gene

PGR :

Progesterone receptor gene

GAPDH :

Glyceraldehyde 3-phosphate dehydrogenase gene

BLI:

Bioluminescence imaging

IC:

Intracardiac

TRAP:

Tartrate resistant acid phosphatase

ANOVA:

Analysis of variance

E2:

17β-estradiol

EWD:

Estrogen withdrawal

MFP:

Mammary fat pad

TBRS :

TGF-β response gene signature

References

  1. Kennecke H, Yerushalmi R, Woods R et al (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28(20):3271–3277

    Article  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  PubMed  CAS  Google Scholar 

  3. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–1564

    Article  PubMed  CAS  Google Scholar 

  4. Kang Y, Siegel PM, Shu W et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3(6):537–549

    Article  PubMed  CAS  Google Scholar 

  5. Gupta GP, Minn AJ, Kang Y et al (2005) Identifying site-specific metastasis genes and functions. Cold Spring Harb Symp Quant Biol 70:149–158

    Article  PubMed  CAS  Google Scholar 

  6. Kang Y (2006) New tricks against an old foe: molecular dissection of metastasis tissue tropism in breast cancer. Breast Dis 26:129–138

    PubMed  CAS  Google Scholar 

  7. Acloque H, Adams MS, Fishwick K et al (2009) Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 119(6):1438–1449

    Article  PubMed  CAS  Google Scholar 

  8. Ganapathy V, Ge R, Grazioli A et al (2010) Targeting the transforming growth factor-beta pathway inhibits human basal-like breast cancer metastasis. Mol Cancer 9(1):122

    Article  PubMed  Google Scholar 

  9. Ge R, Rajeev V, Ray P et al (2006) Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo. Clin Cancer Res 12(14 Pt 1):4315–4330

    Article  PubMed  CAS  Google Scholar 

  10. Korpal M, Yan J, Lu X et al (2009) Imaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med 15(8):960–966

    Article  PubMed  CAS  Google Scholar 

  11. Tan AR, Alexe G, Reiss M (2009) Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Res Treat 115(3):453–495

    Article  PubMed  CAS  Google Scholar 

  12. Bae SN, Arand G, Azzam H et al (1993) Molecular and cellular analysis of basement membrane invasion by human breast cancer cells in matrigel-based in vitro assays. Breast Cancer Res Treat 24(3):241–255

    Article  PubMed  CAS  Google Scholar 

  13. Blick T, Widodo E, Hugo H et al (2008) Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin Exp Metastasis 25(6):629–642

    Article  PubMed  CAS  Google Scholar 

  14. Blick T, Hugo H, Widodo E et al (2010) Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/−) stem cell phenotype in human breast cancer. J Mammary Gland Biol Neoplasia 15(2):235–252

    Article  PubMed  Google Scholar 

  15. Kowalski PJ, Rubin MA, Kleer CG (2003) E-cadherin expression in primary carcinomas of the breast and its distant metastases. Breast Cancer Res 5(6):R217–R222

    Article  PubMed  CAS  Google Scholar 

  16. Bukholm IK, Nesland JM, Borresen-Dale AL (2000) Re-expression of e-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients [seecomments]. J Pathol 190(1):15–19

    Article  PubMed  CAS  Google Scholar 

  17. Weigelt B, Hu Z, He X et al (2005) Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res 65(20):9155–9158

    Article  PubMed  CAS  Google Scholar 

  18. Friedl P, Gilmour D (2009) Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 10(7):445–457

    Article  PubMed  CAS  Google Scholar 

  19. Leu YW, Yan PS, Fan M et al (2004) Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer. Cancer Res 64(22):8184–8192

    Article  PubMed  CAS  Google Scholar 

  20. Fan M, Yan PS, Hartman-Frey C et al (2006) Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res 66(24):11954–11966

    Article  PubMed  CAS  Google Scholar 

  21. Fan M, Long X, Bailey JA et al (2002) The activating enzyme of NEDD8 inhibits steroid receptor function. Mol Endocrinol 16(2):315–330

    Article  PubMed  CAS  Google Scholar 

  22. Parfitt AM, Drezner MK, Glorieux FH et al (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR histomorphometry nomenclature committee. J Bone Miner Res 2(6):595–610

    Article  PubMed  CAS  Google Scholar 

  23. Campbell FC, Blamey RW, Elston CW et al (1981) Oestrogen-receptor status and sites of metastasis in breast cancer. Br J Cancer 44(3):456–459

    Article  PubMed  CAS  Google Scholar 

  24. Shafie SM, Liotta LA (1980) Formation of metastasis by human breast carcinoma cells (MCF-7) in nude mice. Cancer Lett 11(2):81–87

    Article  PubMed  CAS  Google Scholar 

  25. Guise TA, Yin JJ, Mohammad KS (2003) Role of endothelin-1 in osteoblastic bone metastases. Cancer 97(3 Suppl):779–784

    Article  PubMed  Google Scholar 

  26. Osborne CK, Hobbs K, Clark GM (1985) Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic nude mice. Cancer Res 45(2):584–590

    PubMed  CAS  Google Scholar 

  27. Allegra JC, Lippman ME, Thompson EB et al (1979) Relationship between the progesterone, androgen, and glucocorticoid receptor and response rate to endocrine therapy in metastatic breast cancer. Cancer Res 39(6 Pt 1):1973–1979

    PubMed  CAS  Google Scholar 

  28. Clark GM, Sledge GW Jr, Osborne CK et al (1987) Survival from first recurrence: relative importance of prognostic factors in 1,015 breast cancer patients. J Clin Oncol 5(1):55–61

    PubMed  CAS  Google Scholar 

  29. Edery M, Carreau S, Drosdowsky A (1980) In vitro pregnenolone metabolism by mouse adrenal gland: I-estrogen synthesis. Steroids 35(4):381–388

    Article  PubMed  CAS  Google Scholar 

  30. Silberstein GB, Van Horn K, Shyamala G et al (1994) Essential role of endogenous estrogen in directly stimulating mammary growth demonstrated by implants containing pure antiestrogens. Endocrinology 134(1):84–90

    Article  PubMed  CAS  Google Scholar 

  31. Goss P, Allan AL, Rodenhiser DI et al (2008) New clinical and experimental approaches for studying tumor dormancy: does tumor dormancy offer a therapeutic target? APMIS 116(7–8):552–568

    PubMed  CAS  Google Scholar 

  32. Goss PE, Chambers AF (2010) Does tumour dormancy offer a therapeutic target? Nat Rev Cancer 10(12):871–877

    Article  PubMed  CAS  Google Scholar 

  33. Neve RM, Chin K, Fridlyand J et al (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10(6):515–527

    Article  PubMed  CAS  Google Scholar 

  34. Kao J, Salari K, Bocanegra M et al (2009) Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS ONE 4(7):e6146

    Article  PubMed  Google Scholar 

  35. Hollestelle A, Nagel JH, Smid M et al (2010) Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res Treat 121(1):53–64

    Article  PubMed  Google Scholar 

  36. Charafe-Jauffret E, Ginestier C, Monville F et al (2006) Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25(15):2273–2284

    Article  PubMed  CAS  Google Scholar 

  37. Thomas RJ, Guise TA, Yin JJ et al (1999) Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 140(10):4451–4458

    Article  PubMed  CAS  Google Scholar 

  38. Allegra JC, Lippman ME, Thompson EB et al (1980) Estrogen receptor status: an important variable in predicting response to endocrine therapy in metastatic breast cancer. Eur J Cancer 16(3):323–331

    Article  PubMed  CAS  Google Scholar 

  39. Santen RJ, Song RX, Masamura S et al (2008) Adaptation to estradiol deprivation causes up-regulation of growth factor pathways and hypersensitivity to estradiol in breast cancer cells. Adv Exp Med Biol 630:19–34

    Article  PubMed  CAS  Google Scholar 

  40. Mohammad KS, Guise TA (2003) Mechanisms of osteoblastic metastases: role of endothelin-1. Clin Orthop Relat Res (415 Supp):S67–S74

    Article  Google Scholar 

  41. Yin JJ, Mohammad KS, Kakonen SM et al (2003) A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Nat Acad Sci USA 100(19):10954–10959

    Article  PubMed  CAS  Google Scholar 

  42. Harrell JC, Dye WW, Allred DC et al (2006) Estrogen receptor positive breast cancer metastasis: altered hormonal sensitivity and tumor aggressiveness in lymphatic vessels and lymph nodes. Cancer Res 66(18):9308–9315

    Article  PubMed  CAS  Google Scholar 

  43. Harrell JC, Dye WW, Harvell DM et al (2007) Estrogen insensitivity in a model of estrogen receptor positive breast cancer lymph node metastasis. Cancer Res 67(21):10582–10591

    Article  PubMed  CAS  Google Scholar 

  44. Uchino M, Kojima H, Wada K et al (2010) Nuclear beta-catenin and CD44 upregulation characterize invasive cell populations in non-aggressive MCF-7 breast cancer cells. BMC Cancer 10:414

    Article  PubMed  Google Scholar 

  45. Rorth P (2009) Collective cell migration. Annu Rev Cell Dev Biol 25:407–429

    Article  PubMed  CAS  Google Scholar 

  46. Wang Y (2009) Wnt/Planar cell polarity signaling: a new paradigm for cancer therapy. Mol Cancer Ther 8(8):2103–2109

    Article  PubMed  CAS  Google Scholar 

  47. Gamba L, Cubedo N, Ghysen A et al (2010) Estrogen receptor ESR1 controls cell migration by repressing chemokine receptor CXCR4 in the zebrafish posterior lateral line system. Proc Nat Acad Sci USA 107(14):6358–6363

    Article  PubMed  CAS  Google Scholar 

  48. Planas-Silva MD, Bruggeman RD, Grenko RT et al (2006) Role of c-Src and focal adhesion kinase in progression and metastasis of estrogen receptor-positive breast cancer. Biochem Biophys Res Commun 341(1):73–81

    Article  PubMed  CAS  Google Scholar 

  49. Planas-Silva MD, Waltz PK (2007) Estrogen promotes reversible epithelial-to-mesenchymal-like transition and collective motility in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol 104(1–2):11–21

    Article  PubMed  CAS  Google Scholar 

  50. Li Y, Wang JP, Santen RJ et al (2010) Estrogen stimulation of cell migration involves multiple signaling pathway interactions. Endocrinology 151(11):5146–5156

    Article  PubMed  CAS  Google Scholar 

  51. Sanchez AM, Flamini MI, Baldacci C et al (2010) Estrogen receptor-alpha promotes breast cancer cell motility and invasion via focal adhesion kinase and N-WASP. Mol Endocrinol 24(11):2114–2125

    Article  PubMed  CAS  Google Scholar 

  52. Giretti MS, Fu XD, De Rosa G et al (2008) Extra-nuclear signalling of estrogen receptor to breast cancer cytoskeletal remodelling, migration and invasion. PLoS ONE 3(5):e2238

    Article  PubMed  Google Scholar 

  53. Zheng S, Huang J, Zhou K et al (2011) 17beta-estradiol enhances breast cancer cell motility and invasion via extra-nuclear activation of actin-binding protein ezrin. PLoS ONE 6(7):e22439

    Article  PubMed  CAS  Google Scholar 

  54. Chakravarty D, Nair SS, Santhamma B et al (2010) Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells. Cancer Res 70(10):4092–4101

    Article  PubMed  CAS  Google Scholar 

  55. Bierie B, Chung CH, Parker JS et al (2009) Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer. J Clin Invest 119(6):1571–1582

    Article  PubMed  CAS  Google Scholar 

  56. Sahai E (2007) Illuminating the metastatic process. Nat Rev Cancer 7(10):737–749

    Article  PubMed  CAS  Google Scholar 

  57. Giampieri S, Manning C, Hooper S et al (2009) Localized and reversible TGF beta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol 11(11):1287–1296

    Article  PubMed  CAS  Google Scholar 

  58. Giampieri S, Pinner S, Sahai E (2010) Intravital imaging illuminates transforming growth factor beta signaling switches during metastasis. Cancer Res 70(9):3435–3439

    Article  PubMed  CAS  Google Scholar 

  59. Forrester E, Chytil A, Bierie B et al (2005) Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res 65(6):2296–2302

    Article  PubMed  CAS  Google Scholar 

  60. Bierie B, Stover DG, Abel TW et al (2008) Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. Cancer Res 68(6):1809–1819

    Article  PubMed  CAS  Google Scholar 

  61. Yang L, Huang J, Ren X et al (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1 + CD11b + myeloid cells that promote metastasis. Cancer Cell 13(1):23–35

    Article  PubMed  CAS  Google Scholar 

  62. Kareddula A, Zachariah E, Notterman D et al (2008) Transforming growth factor-β signaling strength determines target gene expression profile in human keratinocytes. J Epithel Biol Pharmacol 1:40–94

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by PHS R01 CA120623 award from the National Cancer Institute, National Institutes of Health, US to M.R and by the Histology & Imaging, Bioinformatics and Preclinical Imaging Shared Resources of The Cancer Institute of New Jersey (P30 CA 72720). We wish to express our gratitude to Dr. Kenneth Nephew (Indiana University) for generously sharing his MCF-7 derived cell lines, and to Dr. Yibin Kang (Princeton University) for MDA-MB-231 and SCP2 cells.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, UMDNJ-Robert Wood Johnson Medical School and The Cancer Institute of New Jersey, Room 2007, 195 Little Albany Street, New Brunswick, NJ, 08903, USA

    Vidya Ganapathy, Whitney Banach-Petrosky, Wen Xie, Aparna Kareddula & Michael Reiss

  2. University Medical Center Groningen, 9700 RB, Groningen, Netherlands

    Hilde Nienhuis

  3. Bioinformatics Shared Resource, Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA

    Gregory Miles

Authors
  1. Vidya Ganapathy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Whitney Banach-Petrosky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aparna Kareddula
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hilde Nienhuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gregory Miles
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Reiss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Reiss.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10585_2012_9466_MOESM1_ESM.tif

Supplemental Fig. 1. Local tumor growth following intratibia tumor cell injection. MCF-7-derived bone tropic MCF-7-5624 cells were injected into tibiae of nude mice. Tumor growth was monitored in vivo using microCT and BLI. Tumor lesions retained ERα expression, and were characterized by a highly epithelioid phenotype, as demonstrated by expression of cytokeratins (pan-CK) and membrane associated E-cadherin. Moreover, these lesions induced a predominantly osteoblastic response of the surrounding bone, as shown by orange G and phloxine positivity (a measure of new bone formation), while there was little to no evidence of osteolytic activity (TRAP negativity). Comparison was made with the SCP2 bone tropic subclone of the basal-like ERα-negative human breast cancer line, MDA-MB-231. When injected into the tibia, SCP2 cells also gave rise to bone lesions with a phenotype that was quite distinct from that of MCF-7-5624: None of the cells expressed ERα or PR (not shown). In addition, SCP2-induced lesions were associated with significant osteolysis, as evidenced by strong TRAP positivity. Thirdly, SCP2-derived tumors were distinctly less epithelioid as pan-cytokeratin expression was significantly weaker than in MCF-7-5624 lesions and they failed to express E-cadherin on. Supplementary material 1 (TIFF 93765 kb)

10585_2012_9466_MOESM2_ESM.tif

Supplementary Fig. 2. Locoregional tumor cell dissemination via retroperitoneal lymphatic channels. A. BLI demonstrated that tumors that arose following intra-tibia inoculation of MCF-7-5624A-GF cells disseminated regionally via the iliac and retroperitoneal lymph node chain. B. Solid cords of tumor cells could be seen in local lymphatic channels in the vicinity of the initial tibia lesions. C. Solid cords of tumor cells are also seen to fill retroperitoneal lymphatic channels and lymph nodes. Ly Ch: Lymphatic channel; Ly No: Lymph node. Supplementary material 2 (TIFF 201227 kb)

10585_2012_9466_MOESM3_ESM.tif

Supplementary Fig. 3. Luminal breast cancer cells disseminate as cohesive epithelial clusters. Metastatic MCF-7-5624A-GF cell deposits in the lymphatic vessels, heart and lungs all strongly expressed E-cadherin at the cell membrane, indicating that these tumor cells retain cohesiveness throughout the process of dissemination. Supplementary material 3 (TIFF 92846 kb)

10585_2012_9466_MOESM4_ESM.tif

Supplementary Fig. 4. 17β-estradiol stimulates migration of luminal breast cancer cells. Confluent cultures of ERα-positive luminal human breast cancer cells were wounded using a sterile plastic pipet tip. A. The resulting wound was photographed at multiple sites and the wound area calculated using Image J. Tumor cells migrate collectively to close the gap. B. Treatment with 17β-estradiol resulted in a marked acceleration of wound closure compared to treatment with vehicle only (p=0.0045, t test with Welch correction). Supplementary material 4 (TIFF 87528 kb)

10585_2012_9466_MOESM5_ESM.tif

Supplementary Fig. 5. Histopathology of systemic metastatic lesions. Representative examples of MCF-7-5624A-GF-derived metastases to the skeleton, adrenal glands, central nervous system, lungs, muscle, lymph nodes and mammary gland (Photomicrographs 200x). Supplementary material 5 (TIFF 92705 kb)

10585_2012_9466_MOESM6_ESM.tif

Supplementary Fig. 6. Tumor dormancy in estrogen-deficient animals. Ovariectomized mice were inoculated systemically with MCF-7-5624A-GF cells. At 10 weeks post-inoculation, a small number of metastatic lesions in adrenal glands and mammary fatpads were detectable by BLI (Baseline) (see Figure 4). We then introduced E2 pellets into these animals (Figure 4B). Subsequently, several additional metastases appeared in the skeleton and adrenal glands, indicating that tumor cells had initially seeded those areas and had remained viable but dormant, presumably because of a lack of estrogen. Supplementary material 6 (TIFF 92933 kb)

10585_2012_9466_MOESM7_ESM.xls

Supplemental Table 1. Genes differentially expressed between MCF-7 parental cells and metastatic MCF-7-5624A-GF cells. Gene expression profiling experiments were run in triplicate on the Affymetrix Human Exon 1.0 ST exon microarray platform (1.4 million probes). Using GeneSpring GX 11.5.1 (Agilent Technologies, Inc., Santa Clara, CA, USA), raw exon expression signals were combined and summarized with ExonRMA16 (RMA) using all transcripts (28,829 transcript clusters from RefSeq and full-length GenBank mRNAs). The data were quantile normalized with baseline transformation by the median of all samples. Furthermore, the normalized expression signals were averaged between biological replicates. Gene expression data were first filtered by 10th percentile cut-off, resulting in removal of genes with low signal. The 336 genes shown to be differentially expressed between MCF-7-5624A-GF and MCF-7 parental cells were identified by looking for a significant fold change of >2.0 and an unpaired t test p value with Benjamini Hochberg FDR correction of <0.05. Supplementary material 7 (XLS 124 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ganapathy, V., Banach-Petrosky, W., Xie, W. et al. Luminal breast cancer metastasis is dependent on estrogen signaling. Clin Exp Metastasis 29, 493–509 (2012). https://doi.org/10.1007/s10585-012-9466-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-012-9466-4

Keywords

Search

Navigation