Skip to main content

Advertisement

SpringerLink
Log in

The Interrelating Dynamics of Hypoxic Tumor Microenvironments and Cancer Cell Phenotypes in Cancer Metastasis

  • Published:
Cancer Microenvironment

Abstract

The interrelating dynamics of the primary tumor cells and their surrounding microenvironment might determine phenotypic characteristics of disseminated tumor cells and contribute to cancer metastasis. Cytoprotective mechanisms (e.g., energy metabolism control, DNA damage response, global translation control and unfolded protein response) exert selective pressure in the tumor microenvironment. In particular, adaptation to hypoxia is vital for survival of malignant cells in the tumor and at distant sites such as the bone marrow. In addition to the stress response, the ability of tumor cells to undergo certain cellular re-differentiation programmes like the epithelial-mesenchymal transition (EMT), which is linked to cancer stemness, appears to be important for successful cancer cell spread. Here we will discuss the selection pressures that eventually lead to the formation of overt metastases. We will focus the properties of the microenvironment including (i) metabolic and cytoprotective programs that ensure survival of disseminated tumor cells, (ii) blood vessel structure, and (iii) the hypoxia-normoxia switch as well as intrinsic factors affecting the evolvement of novel tumor cell populations.

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

Similar content being viewed by others

Abbreviations

ATF6:

activating transcription factor 6

CTC:

circulating tumor cells

CXCR4:

C-X-C chemokine receptor 4

DTC:

disseminated tumor cells

EGFR:

epidermal growth factor receptor

EIF2:

eukaryotic initiation factor 2

EMT:

epithelial-mesenchymal transition

ER:

endoplasmatic reticulum

HIF-1:

hypoxia inducible factor 1

HR:

homologous recombination

IRE1:

inositol-requiring protein 1

MET:

mesenchymal-epithelial transition

NHEJ:

non-homologous end joining

PDI:

protein disulfide isomerase

PERK:

PKR-like ER kinase

PTEN:

phosphatase and tensin homolog

ROS:

reactive oxygen species

RTK:

receptor tyrosine kinase

SDF1:

stromal cell-derived factor 1

UPR:

unfolded protein response

References

  1. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  2. Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4:448–456

    Article  PubMed  CAS  Google Scholar 

  3. Ranganathan AC, Adam AP, Zhang L, Aguirre-Ghiso JA (2006) Tumor cell dormancy induced by p38SAPK and ER-stress signaling: an adaptive advantage for metastatic cells? Cancer Biol Ther 5:729–735

    Article  PubMed  CAS  Google Scholar 

  4. Braun S, Kentenich C, Janni W, Hepp F et al (2000) Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. J Clin Oncol 18:80–86

    PubMed  CAS  Google Scholar 

  5. Riethdorf S, Wikman H, Pantel K (2008) Review: Biological relevance of disseminated tumor cells in cancer patients. Int J Cancer 123:1991–2006

    Article  PubMed  CAS  Google Scholar 

  6. Solakoglu O, Maierhofer C, Lahr G, Breit E et al (2002) Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proc Natl Acad Sci U S A 99:2246–2251

    Article  PubMed  CAS  Google Scholar 

  7. Pantel K, Schlimok G, Angstwurm M, Weckermann D et al (1994) Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. J Hematother 3:165–173

    Article  PubMed  CAS  Google Scholar 

  8. Cameron MD, Schmidt EE, Kerkvliet N, Nadkarni KV et al (2000) Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res 60:2541–2546

    PubMed  CAS  Google Scholar 

  9. Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N et al (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153:865–873

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Pantel K, Brakenhoff RH, Brandt B (2008) Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8:329–340

    Article  PubMed  CAS  Google Scholar 

  12. Gatenby RA, Gillies RJ (2008) A microenvironmental model of carcinogenesis. Nat Rev Cancer 8:56–61

    Article  PubMed  CAS  Google Scholar 

  13. Korsching E, Jeffrey SS, Meinerz W, Decker T et al (2008) Basal carcinoma of the breast revisited: an old entity with new interpretations. J Clin Pathol 61:553–560

    Article  PubMed  CAS  Google Scholar 

  14. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142

    Article  PubMed  CAS  Google Scholar 

  15. Bergfeld SA, DeClerck YA (2010) Bone marrow-derived mesenchymal stem cells and the tumor microenvironment. Canc Metastasis Rev 29:249–261.

    Google Scholar 

  16. Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8:705–713

    Article  PubMed  CAS  Google Scholar 

  17. Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252

    Article  PubMed  CAS  Google Scholar 

  18. Agelopoulos K, Greve B, Schmidt H, Pospisil H et al (2010) Selective regain of egfr gene copies in CD44+/CD24−/low breast cancer cellular model MDA-MB-468. BMC Cancer 10:78.

    Google Scholar 

  19. Dachs GU, Tozer GM (2000) Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation. Eur J Cancer 36:1649–1660

    Article  PubMed  CAS  Google Scholar 

  20. Coghlin C, Murray GI (2010) Current and emerging concepts in tumour metastasis. J Pathol 222:1–15.

    Google Scholar 

  21. Brahimi-Horn MC, Chiche J, Pouyssegur J (2007) Hypoxia and cancer. J Mol Med 85:1301–1307

    Article  PubMed  Google Scholar 

  22. Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465

    PubMed  CAS  Google Scholar 

  23. Kallinowski F, Vaupel P, Runkel S, Berg G et al (1988) Glucose uptake, lactate release, ketone body turnover, metabolic micromilieu, and pH distributions in human breast cancer xenografts in nude rats. Cancer Res 48:7264–7272

    PubMed  CAS  Google Scholar 

  24. Bertout JA, Patel SA, Simon MC (2008) The impact of O2 availability on human cancer. Nat Rev Cancer 8:967–975

    Article  PubMed  CAS  Google Scholar 

  25. Ward JP (2008) Oxygen sensors in context. Biochim Biophys Acta 1777:1–14

    Article  PubMed  CAS  Google Scholar 

  26. Noiva R (1999) Protein disulfide isomerase: the multifunctional redox chaperone of the endoplasmic reticulum. Semin Cell Dev Biol 10:481–493

    Article  PubMed  CAS  Google Scholar 

  27. Warburg O (1956) On respiratory impairment in cancer cells. Science 124:269–270

    PubMed  CAS  Google Scholar 

  28. Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441:437–443

    Article  PubMed  CAS  Google Scholar 

  29. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  PubMed  CAS  Google Scholar 

  30. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197

    Article  PubMed  CAS  Google Scholar 

  31. Graber TE, Holcik M (2007) Cap-independent regulation of gene expression in apoptosis. Mol Biosyst 3:825–834

    Article  PubMed  CAS  Google Scholar 

  32. Baird NA, Turnbull DW, Johnson EA (2006) Induction of the heat shock pathway during hypoxia requires regulation of heat shock factor by hypoxia-inducible factor-1. J Biol Chem 281:38675–38681

    Article  PubMed  CAS  Google Scholar 

  33. Wouters BG, Koritzinsky M (2008) Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 8:851–864

    Article  PubMed  CAS  Google Scholar 

  34. Baird SD, Turcotte M, Korneluk RG, Holcik M (2006) Searching for IRES. RNA 12:1755–1785

    Article  PubMed  CAS  Google Scholar 

  35. Rao RV, Peel A, Logvinova A, del Rio G et al (2002) Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett 514:122–128

    Article  PubMed  CAS  Google Scholar 

  36. Rzymski T, Harris AL (2007) The unfolded protein response and integrated stress response to anoxia. Clin Cancer Res 13:2537–2540

    Article  PubMed  CAS  Google Scholar 

  37. Connolly E, Braunstein S, Formenti S, Schneider RJ (2006) Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells. Mol Cell Biol 26:3955–3965

    Article  PubMed  CAS  Google Scholar 

  38. Papandreou I, Krishna C, Kaper F, Cai D et al (2005) Anoxia is necessary for tumor cell toxicity caused by a low-oxygen environment. Cancer Res 65:3171–3178

    PubMed  CAS  Google Scholar 

  39. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995–4004

    Article  PubMed  CAS  Google Scholar 

  40. Zhong H, Chiles K, Feldser D, Laughner E et al (2000) Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60:1541–1545

    PubMed  CAS  Google Scholar 

  41. Pore N, Jiang Z, Shu HK, Bernhard E et al (2006) Akt1 activation can augment hypoxia-inducible factor-1alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway. Mol Cancer Res 4:471–479

    Article  PubMed  CAS  Google Scholar 

  42. Sheta EA, Trout H, Gildea JJ, Harding MA, Theodorescu D (2001) Cell density mediated pericellular hypoxia leads to induction of HIF-1alpha via nitric oxide and Ras/MAP kinase mediated signaling pathways. Oncogene 20:7624–7634

    Article  PubMed  CAS  Google Scholar 

  43. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH et al (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14:34–44

    PubMed  CAS  Google Scholar 

  44. Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9:302–312

    Article  PubMed  CAS  Google Scholar 

  45. Zhang XH, Wang Q, Gerald W, Hudis CA et al (2009) Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16:67–78

    Article  PubMed  CAS  Google Scholar 

  46. Pantel K, Schlimok G, Braun S, Kutter D et al (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 85:1419–1424

    Article  PubMed  CAS  Google Scholar 

  47. Hemsen A, Riethdorf L, Brunner N, Berger J et al (2003) Comparative evaluation of urokinase-type plasminogen activator receptor expression in primary breast carcinomas and on metastatic tumor cells. Int J Cancer 107:903–909

    Article  PubMed  CAS  Google Scholar 

  48. Klein CA, Seidl S, Petat-Dutter K, Offner S et al (2002) Combined transcriptome and genome analysis of single micrometastatic cells. Nat Biotechnol 20:387–392

    Article  PubMed  CAS  Google Scholar 

  49. Thurm H, Ebel S, Kentenich C, Hemsen A et al (2003) Rare expression of epithelial cell adhesion molecule on residual micrometastatic breast cancer cells after adjuvant chemotherapy. Clin Cancer Res 9:2598–2604

    PubMed  CAS  Google Scholar 

  50. Talmadge JE (2007) Clonal selection of metastasis within the life history of a tumor. Cancer Res 67:11471–11475

    Article  PubMed  CAS  Google Scholar 

  51. Polyak K, Hahn WC (2006) Roots and stems: stem cells in cancer. Nat Med 12:296–300

    Article  PubMed  CAS  Google Scholar 

  52. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  PubMed  CAS  Google Scholar 

  53. Berx G, Raspe E, Christofori G, Thiery JP, Sleeman JP (2007) Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. Clin Exp Metastasis 24:587–597

    Article  PubMed  CAS  Google Scholar 

  54. Pantel K, Alix-Panabieres C, Riethdorf S (2009) Cancer micrometastases. Nat Rev Clin Oncol 6:339–351

    Article  PubMed  CAS  Google Scholar 

  55. Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7:834–846

    Article  PubMed  CAS  Google Scholar 

  56. Hanrahan EO, Gonzalez-Angulo AM, Giordano SH, Rouzier R et al (2007) Overall survival and cause-specific mortality of patients with stage T1a, bN0M0 breast carcinoma. J Clin Oncol 25:4952–4960

    Article  PubMed  Google Scholar 

  57. Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904

    Article  PubMed  CAS  Google Scholar 

  58. Xie K, Huang S (2003) Regulation of cancer metastasis by stress pathways. Clin Exp Metastasis 20:31–43

    Article  PubMed  CAS  Google Scholar 

  59. Kingsley LA, Fournier PG, Chirgwin JM, Guise TA (2007) Molecular biology of bone metastasis. Mol Cancer Ther 6:2609–2617

    Article  PubMed  CAS  Google Scholar 

  60. Ranganathan AC, Zhang L, Adam AP, Aguirre-Ghiso JA (2006) Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res 66:1702–1711

    Article  PubMed  CAS  Google Scholar 

  61. Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505–516

    Article  PubMed  CAS  Google Scholar 

  62. Norton L, Massague J (2006) Is cancer a disease of self-seeding? Nat Med 12:875–878

    Article  PubMed  CAS  Google Scholar 

  63. Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284

    Article  PubMed  CAS  Google Scholar 

  64. Kim MY, Oskarsson T, Acharyya S, Nguyen DX et al (2009) Tumor self-seeding by circulating cancer cells. Cell 139:1315–1326

    Article  PubMed  Google Scholar 

  65. Aird WC (2007) Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 100:158–173

    Article  PubMed  CAS  Google Scholar 

  66. Aird WC (2007) Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res 100:174–190

    Article  PubMed  CAS  Google Scholar 

  67. Kopp HG, Avecilla ST, Hooper AT, Rafii S (2005) The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology (Bethesda) 20:349–356

    Article  CAS  Google Scholar 

  68. Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M et al (2003) From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci U S A 100:7737–7742

    Article  PubMed  CAS  Google Scholar 

  69. Engelhardt B, Sorokin L (2009) The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31:497–511

    Article  PubMed  Google Scholar 

  70. Andres AC, Djonov V (2010) The mammary gland vasculature revisited. J Mammary Gland Biol Neoplasia 15:319–328.

    Google Scholar 

  71. Djonov V, Andres AC, Ziemiecki A (2001) Vascular remodelling during the normal and malignant life cycle of the mammary gland. Microsc Res Tech 52:182–189

    Article  PubMed  CAS  Google Scholar 

  72. Silva AS, Gatenby RA, Gillies RJ, Yunes JA (2010) A quantitative theoretical model for the development of malignancy in ductal carcinoma in situ. J Theor Biol 262:601–613.

    Google Scholar 

  73. Safali M, Karslioglu Y, Arpaci F, Kurt B, Gunhan O (2010) A distinct microvascular pattern accompanied by aggressive clinical course in breast carcinomas: a fact or a coincidence? Pathol Res Pract 206:93–97.

    Google Scholar 

  74. Banerjee S, Dowsett M, Ashworth A, Martin LA (2007) Mechanisms of disease: angiogenesis and the management of breast cancer. Nat Clin Pract Oncol 4:536–550

    Article  PubMed  CAS  Google Scholar 

  75. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273

    Article  PubMed  CAS  Google Scholar 

  76. Meng S, Tripathy D, Frenkel EP, Shete S et al (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10:8152–8162

    Article  PubMed  Google Scholar 

  77. Muller V, Alix-Panabieres C, Pantel K (2010) Insights into minimal residual disease in cancer patients: implications for anti-cancer therapies. Eur J Cancer 46:1189–1197.

    Google Scholar 

  78. Schardt JA, Meyer M, Hartmann CH, Schubert F et al (2005) Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell 8:227–239

    Article  PubMed  CAS  Google Scholar 

  79. Young SD, Marshall RS, Hill RP (1988) Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci U S A 85:9533–9537

    Article  PubMed  CAS  Google Scholar 

  80. Rofstad EK, Gaustad JV, Egeland TA, Mathiesen B, Galappathi K (2010) Tumors exposed to acute cyclic hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination. Int J Cancer 127:1535–1546.

    Google Scholar 

  81. Walenta S, Wetterling M, Lehrke M, Schwickert G et al (2000) High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res 60:916–921

    PubMed  CAS  Google Scholar 

  82. Freiberg RA, Krieg AJ, Giaccia AJ, Hammond EM (2006) Checking in on hypoxia/reoxygenation. Cell Cycle 5:1304–1307

    Article  PubMed  CAS  Google Scholar 

  83. Bindra RS, Gibson SL, Meng A, Westermark U et al (2005) Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res 65:11597–11604

    Article  PubMed  CAS  Google Scholar 

  84. Kang MJ, Jung SM, Kim MJ, Bae JH et al (2008) DNA-dependent protein kinase is involved in heat shock protein-mediated accumulation of hypoxia-inducible factor-1alpha in hypoxic preconditioned HepG2 cells. FEBS J 275:5969–5981

    Article  PubMed  CAS  Google Scholar 

  85. Ameri K, Luong R, Zhang H, Powell AA et al (2010) Circulating tumour cells demonstrate an altered response to hypoxia and an aggressive phenotype. Br J Cancer 102:561–569.

    Google Scholar 

  86. Kallergi G, Markomanolaki H, Giannoukaraki V, Papadaki MA et al (2009) Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients. Breast Cancer Res 11:R84

    Article  PubMed  CAS  Google Scholar 

  87. Risom L, Lundby C, Thomsen JJ, Mikkelsen L et al (2007) Acute hypoxia and reoxygenation-induced DNA oxidation in human mononuclear blood cells. Mutat Res 625:125–133

    Article  PubMed  CAS  Google Scholar 

  88. Chen Y, Azad MB, Gibson SB (2009) Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ 16:1040–1052

    Article  PubMed  CAS  Google Scholar 

  89. Azad MB, Chen Y, Gibson SB (2009) Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment. Antioxid Redox Signal 11:777–790

    Article  PubMed  CAS  Google Scholar 

  90. Pires IM, Bencokova Z, Milani M, Folkes LK et al (2010) Effects of acute versus chronic hypoxia on DNA damage responses and genomic instability. Cancer Res 70:925–935.

    Google Scholar 

  91. Chan N, Pires IM, Bencokova Z, Coackley C et al (2010) Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. Cancer Res 70:8045–8054.

    Google Scholar 

  92. Hammond EM, Dorie MJ, Giaccia AJ (2003) ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. J Biol Chem 278:12207–12213

    Article  PubMed  CAS  Google Scholar 

  93. Chow DC, Wenning LA, Miller WM, Papoutsakis ET (2001) Modeling pO(2) distributions in the bone marrow hematopoietic compartment. II. Modified Kroghian models. Biophys J 81:685–696

    Article  PubMed  CAS  Google Scholar 

  94. Muller V, Stahmann N, Riethdorf S, Rau T et al (2005) Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res 11:3678–3685

    Article  PubMed  Google Scholar 

  95. Bryan BB, Schnitt SJ, Collins LC (2006) Ductal carcinoma in situ with basal-like phenotype: a possible precursor to invasive basal-like breast cancer. Mod Pathol 19:617–621

    Article  PubMed  CAS  Google Scholar 

  96. Cheang MCU, Voduc D, Bajdik C, Leung S et al (2008) Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14:1368–1376

    Article  PubMed  CAS  Google Scholar 

  97. Lacroix M, Leclercq G (2004) Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat 83:249–289

    Article  PubMed  CAS  Google Scholar 

  98. Putz E, Witter K, Offner S, Stosiek P et al (1999) Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. Cancer Res 59:241–248

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  100. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R (1982) The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31:11–24

    Article  PubMed  CAS  Google Scholar 

  101. Bocker W, Moll R, Poremba C, Holland R et al (2002) Common adult stem cells in the human breast give rise to glandular and myoepithelial cell lineages: a new cell biological concept. Lab Invest 82:737–746

    PubMed  Google Scholar 

  102. Korsching E, Packeisen J, Agelopoulos K, Eisenacher M et al (2002) Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis. Lab Invest 82:1525–1533

    PubMed  CAS  Google Scholar 

  103. Korsching E, Packeisen J, Liedtke C, Hungermann D et al (2005) The origin of vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J Pathol 206:451–457

    Article  PubMed  CAS  Google Scholar 

  104. Shipitsin M, Polyak K (2008) The cancer stem cell hypothesis: in search of definitions, markers, and relevance. Lab Invest 88:459–463

    Article  PubMed  CAS  Google Scholar 

  105. Trumpp A, Wiestler OD (2008) Mechanisms of disease: cancer stem cells–targeting the evil twin. Nat Clin Pract Oncol 5:337–347

    PubMed  CAS  Google Scholar 

  106. Clarke MF, Fuller M (2006) Stem cells and cancer: two faces of eve. Cell 124:1111–1115

    Article  PubMed  CAS  Google Scholar 

  107. Marotta LL, Polyak K (2009) Cancer stem cells: a model in the making. Curr Opin Genet Dev 19:44–50

    Article  PubMed  CAS  Google Scholar 

  108. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983–3988

    Article  PubMed  CAS  Google Scholar 

  109. Al-Hajj M, Clarke MF (2004) Self-renewal and solid tumor stem cells. Oncogene 23:7274–7282

    Article  PubMed  CAS  Google Scholar 

  110. Shipitsin M, Campbell LL, Argani P, Weremowicz S et al (2007) Molecular definition of breast tumor heterogeneity. Cancer Cell 11:259–273

    Article  PubMed  CAS  Google Scholar 

  111. Haase VH (2009) Oxygen regulates epithelial-to-mesenchymal transition: insights into molecular mechanisms and relevance to disease. Kidney Int 76:492–499

    Article  PubMed  CAS  Google Scholar 

  112. Lester RD, Jo M, Montel V, Takimoto S, Gonias SL (2007) uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J Cell Biol 178:425–436

    Article  PubMed  CAS  Google Scholar 

  113. Helczynska K, Kronblad A, Jogi A, Nilsson E et al (2003) Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ. Cancer Res 63:1441–1444

    PubMed  CAS  Google Scholar 

  114. Tarin D, Thompson EW, Newgreen DF (2005) The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65:5996–6000, discussion 6000–5991

    Article  PubMed  CAS  Google Scholar 

  115. Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740–746

    Article  PubMed  CAS  Google Scholar 

  116. Brandt BH, Roetger A, Dittmar T, Nikolai G et al (1999) c-erbB-2/EGFR as dominant heterodimerization partners determine a motogenic phenotype in human breast cancer cells. FASEB J 13:1939–1949

    PubMed  CAS  Google Scholar 

  117. Dittmar T, Husemann A, Schewe Y, Nofer JR et al (2002) Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. FASEB J 16:1823–1825

    PubMed  CAS  Google Scholar 

  118. Tanaka H, Shirkoohi R, Nakagawa K, Qiao H et al (2006) siRNA gelsolin knockdown induces epithelial-mesenchymal transition with a cadherin switch in human mammary epithelial cells. Int J Cancer 118:1680–1691

    Article  PubMed  CAS  Google Scholar 

  119. Sleeman JP (2000) The lymph node as a bridgehead in the metastatic dissemination of tumors. Recent Results Cancer Res 157:55–81

    Article  PubMed  CAS  Google Scholar 

  120. van der Pluijm G (2011) Epithelial plasticity, cancer stem cells and bone metastasis formation. Bone 48:37–43.

    Google Scholar 

  121. Mani SA, Guo W, Liao MJ, Eaton EN et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715

    Article  PubMed  CAS  Google Scholar 

  122. Kakarala M, Wicha MS (2008) Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol 26:2813–2820

    Article  PubMed  Google Scholar 

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

    Google Scholar 

  124. Roetger A, Merschjann A, Dittmar T, Jackisch C et al (1998) Selection of potentially metastatic subpopulations expressing c-erbB-2 from breast cancer tissue by use of an extravasation model. Am J Pathol 153:1797–1806

    Article  PubMed  CAS  Google Scholar 

  125. Feldner JC, Brandt BH (2002) Cancer cell motility–on the road from c-erbB-2 receptor steered signaling to actin reorganization. Exp Cell Res 272:93–108

    Article  PubMed  CAS  Google Scholar 

  126. Storci G, Sansone P, Trere D, Tavolari S et al (2008) The basal-like breast carcinoma phenotype is regulated by SLUG gene expression. J Pathol 214:25–37

    Article  PubMed  CAS  Google Scholar 

  127. Alix-Panabieres C, Vendrell JP, Pelle O, Rebillard X et al (2007) Detection and characterization of putative metastatic precursor cells in cancer patients. Clin Chem 53:537–539

    Article  PubMed  CAS  Google Scholar 

  128. Braun S, Hepp F, Sommer HL, Pantel K (1999) Tumor-antigen heterogeneity of disseminated breast cancer cells: implications for immunotherapy of minimal residual disease. Int J Cancer 84:1–5

    Article  PubMed  CAS  Google Scholar 

  129. Slade MJ, Payne R, Riethdorf S, Ward B et al (2009) Comparison of bone marrow, disseminated tumour cells and blood-circulating tumour cells in breast cancer patients after primary treatment. Br J Cancer 100:160–166

    Article  PubMed  CAS  Google Scholar 

  130. Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S et al (2006) CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res 8:R59

    Article  PubMed  CAS  Google Scholar 

  131. Willipinski-Stapelfeldt B, Riethdorf S, Assmann V, Woelfle U et al (2005) Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin Cancer Res 11:8006–8014

    Article  PubMed  CAS  Google Scholar 

  132. Bartkowiak K, Wieczorek M, Buck F, Harder S et al (2009) Two-dimensional differential gel electrophoresis of a cell line derived from a breast cancer micrometastasis revealed a stem/ progenitor cell protein profile. J Proteome Res 8:2004–2014

    Article  PubMed  CAS  Google Scholar 

  133. Bartkowiak K, Effenberger KE, Harder S, Andreas A et al (2010) Discovery of a novel unfolded protein response phenotype of cancer stem/progenitor cells from the bone marrow of breast cancer patients. J Proteome Res 9:3158–3168.

    Google Scholar 

  134. Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD (2007) Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci U S A 104:5431–5436

    Article  PubMed  CAS  Google Scholar 

  135. Pierga JY, Bonneton C, Vincent-Salomon A, de Cremoux P et al (2004) Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 10:1392–1400

    Article  PubMed  CAS  Google Scholar 

  136. Bross ID, Viadana E, Pickren J (1975) Do generalized metastases occur directly from the primary? J Chronic Dis 28:149–159

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Stiftung für Pathobiochemie und Molekulare Diagnostik of the Deutsche Gesellschaft für Klinische Chemie und Laboratoriumsmedizin and by the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n° 202230, acronym GENINCA.

Author information

Authors and Affiliations

  1. Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Kai Bartkowiak, Sabine Riethdorf & Klaus Pantel

Authors
  1. Kai Bartkowiak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabine Riethdorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Klaus Pantel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Klaus Pantel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bartkowiak, K., Riethdorf, S. & Pantel, K. The Interrelating Dynamics of Hypoxic Tumor Microenvironments and Cancer Cell Phenotypes in Cancer Metastasis. Cancer Microenvironment 5, 59–72 (2012). https://doi.org/10.1007/s12307-011-0067-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12307-011-0067-6

Keywords

Search

Navigation