Skip to main content
SpringerLink
Log in

Anti-angiogenic Therapy-Mediated Endothelial Damage: A Driver of Breast Cancer Recurrence?

  • Chapter
  • First Online:
Biological Mechanisms of Minimal Residual Disease and Systemic Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1100))

Abstract

Anti-angiogenic therapy was conceived originally as a silver bullet able to maintain tumor dormancy indefinitely. By targeting new blood vessel formation, anti-angiogenic agents were expected to suppress the growth of any type of primary or metastatic tumor, independent of their subtype or genetic landscape. However, more that 20 years after the first anti-angiogenic preclinical trial, the astonishing inhibition of metastatic outgrowth originally observed in mouse models never translated into clinics. Indeed, whereas anti-angiogenic agents (sometimes) prolong progression-free survival, they fail to impact overall survival, particularly in breast cancer. This observation revealed to be true in early- and advanced-stage breast cancer patients treated either in adjuvant or neo-adjuvant settings, suggesting that the effect of anti-angiogenic therapy on repressing growth of overt metastases – and also on preventing outgrowth of disseminated tumor cells and micrometastases – is limited. What are the reasons underlying this failure? And, more importantly, is there still room for improvement?

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ARP-2/3:

Actin-related protein-2/3

BMP:

Bone morphogenic protein

CCL-2:

CC-chemokine ligand-2

CCR-2:

CC-chemokine receptor-2

CSC:

Cancer stem cell

CTC:

Circulating tumor cell

CXCL-12:

CXC-chemokine ligand-12

CXCR-4:

CXC-chemokine receptor-4

Dll4:

Delta-like protein 4

DTC:

Disseminated tumor cell

EMT:

Epithelial-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

FAK:

Focal adhesion kinase

GAS6:

Growth arrest-specific gene 6

G-CSF:

Granulocyte-colony stimulating factor

HGF:

Hepatocytes growth factor

IGF-1:

Insulin-like growth factor-1

IGF-1R:

Insulin-like growth factor-1 receptor

IGFBP-7:

Insulin-like growth factor binding protein-7

MMP-14:

Matrix metalloproteinase-14

PDGFR:

Platelet-derived growth factor receptor

PVN:

Perivascular niche

SCF:

Stem cell factor

SDF-1:

Stromal cell-derived factor-1

TGF-β:

Transforming growth factor-β

uPAR:

Urokinase-type plasminogen activator receptor

VCAM-1:

Vascular cell adhesion molecule-1

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

References

  1. Aguilera KY, Rivera LB, Hur H, Carbon JG, Toombs JE, Goldstein CD, Dellinger MT, Castrillon DH, Brekken RA (2014) Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma. Cancer Res 74(4):1032–1044. https://doi.org/10.1158/0008-5472.CAN-13-2800

    Article  CAS  PubMed  Google Scholar 

  2. Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7(11):834–846. https://doi.org/10.1038/nrc2256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L (2003) ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 63(7):1684–1695

    CAS  PubMed  Google Scholar 

  4. Aguirre-Ghiso JA, Ossowski L, Rosenbaum SK (2004) Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth. Cancer Res 64(20):7336–7345. https://doi.org/10.1158/0008-5472.CAN-04-0113

    Article  CAS  PubMed  Google Scholar 

  5. Algire GH, Chalkley HW (1945) Vascular reactions of normal and malignant tissue in vivo. I Vascular reactions of mice to wounds and or normal and neoplastic transplants. J Natl Cancer Inst 6:73–85

    Article  Google Scholar 

  6. Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, Feyen K, Tawney J, Hanahan D, Michael IP, Bergers G (2017) Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med 9(385). https://doi.org/10.1126/scitranslmed.aak9679

    Article  PubMed  PubMed Central  Google Scholar 

  7. Allen E, Mieville P, Warren CM, Saghafinia S, Li L, Peng MW, Hanahan D (2016) Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling. Cell Rep 15(6):1144–1160. https://doi.org/10.1016/j.celrep.2016.04.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ang YL, Soo RA, Ho GF, Sundar R, Tan SH, Lim JSJ, Yong W-P, Chong WQ, Ho J, Kumarakulasinghe NB, Aung MI, Koh E, Ramlee M, Phyu PS, Kyin L, Goh BC, Lee S-C (2016) A phase II randomized study of docetaxel +/- low-dose, short course sunitinib in advanced solid tumours. J Clin Oncol 34(15_suppl):e14124–e14124. https://doi.org/10.1200/JCO.2016.34.15_suppl.e14124

    Article  Google Scholar 

  9. Banys M, Solomayer EF, Gebauer G, Janni W, Krawczyk N, Lueck HJ, Becker S, Huober J, Kraemer B, Wackwitz B, Hirnle P, Wallwiener D, Fehm T (2013) Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial. BMC Cancer 13:480. https://doi.org/10.1186/1471-2407-13-480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N (2015) Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. The Lancet Oncol 16(9):1037–1048. https://doi.org/10.1016/S1470-2045(15)00041-8

    Article  CAS  PubMed  Google Scholar 

  11. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N (2012) Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366(4):310–320. https://doi.org/10.1056/NEJMoa1111097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Beck B, Driessens G, Goossens S, Youssef KK, Kuchnio A, Caauwe A, Sotiropoulou PA, Loges S, Lapouge G, Candi A, Mascre G, Drogat B, Dekoninck S, Haigh JJ, Carmeliet P, Blanpain C (2011) A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478(7369):399–403. https://doi.org/10.1038/nature10525

    Article  CAS  PubMed  Google Scholar 

  13. Bell R, Brown J, Parmar M, Toi M, Suter T, Steger GG, Pivot X, Mackey J, Jackisch C, Dent R, Hall P, Xu N, Morales L, Provencher L, Hegg R, Vanlemmens L, Kirsch A, Schneeweiss A, Masuda N, Overkamp F, Cameron D (2017) Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer. Ann Oncol 28(4):754–760

    CAS  PubMed  Google Scholar 

  14. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603. https://doi.org/10.1038/nrc2442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bergh J, Bondarenko IM, Lichinitser MR, Liljegren A, Greil R, Voytko NL, Makhson AN, Cortes J, Lortholary A, Bischoff J, Chan A, Delaloge S, Huang X, Kern KA, Giorgetti C (2012) First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol 30(9):921–929. https://doi.org/10.1200/JCO.2011.35.7376

    Article  CAS  PubMed  Google Scholar 

  16. Bragado P, Estrada Y, Parikh F, Krause S, Capobianco C, Farina HG, Schewe DM, Aguirre-Ghiso JA (2013) TGF-beta2 dictates disseminated tumour cell fate in target organs through TGF-beta-RIII and p38alpha/beta signalling. Nat Cell Biol 15(11):1351–1361. https://doi.org/10.1038/ncb2861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802. https://doi.org/10.1056/NEJMoa050434

    Article  CAS  PubMed  Google Scholar 

  18. Bridgeman VL, Vermeulen PB, Foo S, Bilecz A, Daley F, Kostaras E, Nathan MR, Wan E, Frentzas S, Schweiger T, Hegedus B, Hoetzenecker K, Renyi-Vamos F, Kuczynski EA, Vasudev NS, Larkin J, Gore M, Dvorak HF, Paku S, Kerbel RS, Dome B, Reynolds AR (2017) Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J Pathol 241(3):362–374. https://doi.org/10.1002/path.4845

    Article  CAS  PubMed  Google Scholar 

  19. Brodt P (2016) Role of the microenvironment in liver metastasis: from pre- to prometastatic niches. Clin Cancer Res 22(24):5971–5982. https://doi.org/10.1158/1078-0432.CCR-16-0460

    Article  CAS  PubMed  Google Scholar 

  20. Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O’Neill V, Rugo HS (2011) RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 29(32):4286–4293. https://doi.org/10.1200/JCO.2010.34.1255

    Article  CAS  PubMed  Google Scholar 

  21. Butler JM, Kobayashi H, Rafii S (2010) Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10(2):138–146. https://doi.org/10.1038/nrc2791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M, Frank A, Bayazitov IT, Zakharenko SS, Gajjar A, Davidoff A, Gilbertson RJ (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11(1):69–82. https://doi.org/10.1016/j.ccr.2006.11.020

    Article  CAS  PubMed  Google Scholar 

  23. Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, Steger GG, Suter TM, Toi M, Parmar M, Laeufle R, Im Y-H, Romieu G, Harvey V, Lipatov O, Pienkowski T, Cottu P, Chan A, Im S-A, Hall PS, Bubuteishvili-Pacaud L, Henschel V, Deurloo RJ, Pallaud C, Bell R (2013) Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. The Lancet Oncol 14(10):933–942

    Article  CAS  PubMed  Google Scholar 

  24. Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J, Pircher A, Chaturvedi P, Hol J, Thienpont B, Teuwen LA, Schoors S, Boeckx B, Vriens J, Kuchnio A, Veys K, Cruys B, Finotto L, Treps L, Stav-Noraas TE, Bifari F, Stapor P, Decimo I, Kampen K, De Bock K, Haraldsen G, Schoonjans L, Rabelink T, Eelen G, Ghesquiere B, Rehman J, Lambrechts D, Malik AB, Dewerchin M, Carmeliet P (2016) Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell 30(6):968–985. https://doi.org/10.1016/j.ccell.2016.10.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cao Z, Scandura JM, Inghirami GG, Shido K, Ding BS, Rafii S (2017) Molecular checkpoint decisions made by subverted vascular niche transform indolent tumor cells into chemoresistant cancer stem cells. Cancer Cell 31(1):110–126. https://doi.org/10.1016/j.ccell.2016.11.010

    Article  CAS  PubMed  Google Scholar 

  26. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438(7070):932–936. https://doi.org/10.1038/nature04478

    Article  CAS  PubMed  Google Scholar 

  27. Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10(6):417–427. https://doi.org/10.1038/nrd3455

    Article  CAS  PubMed  Google Scholar 

  28. Casillas AL, Toth RK, Sainz AG, Singh N, Desai AA, Kraft AS, Warfel NA (2017) Hypoxia-inducible PIM kinase expression promotes resistance to antiangiogenic agents. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-17-1318

    Article  PubMed  PubMed Central  Google Scholar 

  29. Charles N, Ozawa T, Squatrito M, Bleau AM, Brennan CW, Hambardzumyan D, Holland EC (2010) Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 6(2):141–152. https://doi.org/10.1016/j.stem.2010.01.001

    Article  CAS  PubMed  Google Scholar 

  30. Christensen JG (2007) A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. Ann Oncol 18(Suppl 10):x3–10. https://doi.org/10.1093/annonc/mdm408

    Article  PubMed  Google Scholar 

  31. Chung AS, Kowanetz M, Wu X, Zhuang G, Ngu H, Finkle D, Komuves L, Peale F, Ferrara N (2012) Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors. J Pathol 227(4):404–416. https://doi.org/10.1002/path.4052

    Article  CAS  PubMed  Google Scholar 

  32. Cohen MH, Shen YL, Keegan P, Pazdur R (2009) FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14(11):1131–1138. https://doi.org/10.1634/theoncologist.2009-0121

    Article  CAS  PubMed  Google Scholar 

  33. Conley SJ, Baker TL, Burnett JP, Theisen RL, Lazarus D, Peters CG, Clouthier SG, Eliasof S, Wicha MS (2015) CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, targets cancer stem cells and impedes resistance to antiangiogenic therapy in mouse models of breast cancer. Breast Cancer Res Treat 150(3):559–567. https://doi.org/10.1007/s10549-015-3349-8

    Article  CAS  PubMed  Google Scholar 

  34. Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG, Wicha MS (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A 109(8):2784–2789. https://doi.org/10.1073/pnas.1018866109

    Article  PubMed  PubMed Central  Google Scholar 

  35. Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, Sugimoto H, Rocha RM, Damascena A, Brentani RR, Kalluri R (2012) Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21(1):66–81. https://doi.org/10.1016/j.ccr.2011.11.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Crown JP, Dieras V, Staroslawska E, Yardley DA, Bachelot T, Davidson N, Wildiers H, Fasching PA, Capitain O, Ramos M, Greil R, Cognetti F, Fountzilas G, Blasinska-Morawiec M, Liedtke C, Kreienberg R, Miller WH Jr, Tassell V, Huang X, Paolini J, Kern KA, Romieu G (2013) Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol 31(23):2870–2878. https://doi.org/10.1200/JCO.2012.43.3391

    Article  CAS  PubMed  Google Scholar 

  37. Curigliano G, Pivot X, Cortes J, Elias A, Cesari R, Khosravan R, Collier M, Huang X, Cataruozolo PE, Kern KA, Goldhirsch A (2013) Randomized phase II study of sunitinib versus standard of care for patients with previously treated advanced triple-negative breast cancer. Breast (Edinburgh, Scotland) 22(5):650–656

    Article  Google Scholar 

  38. De Cock JM, Shibue T, Dongre A, Keckesova Z, Reinhardt F, Weinberg RA (2016) Inflammation triggers Zeb1-dependent escape from tumor latency. Cancer Res 76(23):6778–6784. https://doi.org/10.1158/0008-5472.CAN-16-0608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Decker AM, Jung Y, Cackowski FC, Yumoto K, Wang J, Taichman RS (2017) Sympathetic signaling reactivates quiescent disseminated prostate cancer cells in the bone marrow. Mol Cancer Res: MCR 15(12):1644–1655. https://doi.org/10.1158/1541-7786.MCR-17-0132

    Article  CAS  PubMed  Google Scholar 

  40. Dickler MN, Barry WT, Cirrincione CT, Ellis MJ, Moynahan ME, Innocenti F, Hurria A, Rugo HS, Lake DE, Hahn O, Schneider BP, Tripathy D, Carey LA, Winer EP, Hudis CA (2016) Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer: CALGB 40503 (Alliance). J Clin Oncol 34(22):2602–2609. https://doi.org/10.1200/JCO.2015.66.1595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dieras V, Wildiers H, Jassem J, Dirix LY, Guastalla JP, Bono P, Hurvitz SA, Goncalves A, Romieu G, Limentani SA, Jerusalem G, Lakshmaiah KC, Roche H, Sanchez-Rovira P, Pienkowski T, Segui Palmer MA, Li A, Sun YN, Pickett CA, Slamon DJ (2015) Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: A phase 2 randomized study. Breast 24(3):182–190. https://doi.org/10.1016/j.breast.2014.11.003

    Article  PubMed  Google Scholar 

  42. Ding BS, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, Mittal V, Kobayashi H, Shido K, Lyden D, Sato TN, Rabbany SY, Rafii S (2010) Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468(7321):310–315. https://doi.org/10.1038/nature09493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ding BS, Nolan DJ, Guo P, Babazadeh AO, Cao Z, Rosenwaks Z, Crystal RG, Simons M, Sato TN, Worgall S, Shido K, Rabbany SY, Rafii S (2011) Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. Cell 147(3):539–553. https://doi.org/10.1016/j.cell.2011.10.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z, Bergers G (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13(3):206–220. https://doi.org/10.1016/j.ccr.2008.01.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Gounaris I, Abraham JE, Hughes-Davies L, McAdam K, Chan S, Ahmad R, Hickish T, Rea D, Caldas C, Bartlett JMS, Cameron DA, Provenzano E, Thomas J, Hayward RL, Group ARI (2017) Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial. Ann Oncol 28(8):1817–1824. https://doi.org/10.1093/annonc/mdx173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ebos JM, Kerbel RS (2011) Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 8(4):210–221. https://doi.org/10.1038/nrclinonc.2011.21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS (2007) Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A 104(43):17069–17074. https://doi.org/10.1073/pnas.0708148104

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15(3):232–239. https://doi.org/10.1016/j.ccr.2009.01.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ebos JM, Mastri M, Lee CR, Tracz A, Hudson JM, Attwood K, Cruz-Munoz WR, Jedeszko C, Burns P, Kerbel RS (2014) Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy. EMBO Mol Med 6(12):1561–1576. https://doi.org/10.15252/emmm.201403989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ehrmann RL, Knoth M (1968) Choriocarcinoma. Transfilter stimulation of vasoproliferation in the hamster cheek pouch. Studied by light and electron microscopy. J Natl Cancer Inst 41(6):1329–1341

    CAS  PubMed  Google Scholar 

  51. Elice F, Rodeghiero F (2010) Bleeding complications of antiangiogenic therapy: pathogenetic mechanisms and clinical impact. Thromb Res 125(Suppl 2):S55–S57. https://doi.org/10.1016/S0049-3848(10)70014-1

    Article  PubMed  Google Scholar 

  52. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM (2009) Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 27(20):3312–3318. https://doi.org/10.1200/JCO.2008.19.5511

    Article  CAS  PubMed  Google Scholar 

  53. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N, AT Investigators (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370(9605):2103–2111. https://doi.org/10.1016/S0140-6736(07)61904-7

    Article  PubMed  Google Scholar 

  54. Fantozzi A, Gruber DC, Pisarsky L, Heck C, Kunita A, Yilmaz M, Meyer-Schaller N, Cornille K, Hopfer U, Bentires-Alj M, Christofori G (2014) VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation. Cancer Res 74(5):1566–1575. https://doi.org/10.1158/0008-5472.CAN-13-1641

    Article  CAS  PubMed  Google Scholar 

  55. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3(5):391–400. https://doi.org/10.1038/nrd1381

    Article  CAS  PubMed  Google Scholar 

  56. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186. https://doi.org/10.1056/NEJM197111182852108

    Article  CAS  PubMed  Google Scholar 

  57. Franco M, Roswall P, Cortez E, Hanahan D, Pietras K (2011) Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression. Blood 118(10):2906–2917. https://doi.org/10.1182/blood-2011-01-331694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, Nathan M, Wotherspoon A, Gao ZH, Shi Y, Van den Eynden G, Daley F, Peckitt C, Tan X, Salman A, Lazaris A, Gazinska P, Berg TJ, Eltahir Z, Ritsma L, Van Rheenen J, Khashper A, Brown G, Nystrom H, Sund M, Van Laere S, Loyer E, Dirix L, Cunningham D, Metrakos P, Reynolds AR (2016) Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med 22(11):1294–1302. https://doi.org/10.1038/nm.4197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gao H, Chakraborty G, Lee-Lim AP, Mo Q, Decker M, Vonica A, Shen R, Brogi E, Brivanlou AH, Giancotti FG (2012) The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150(4):764–779. https://doi.org/10.1016/j.cell.2012.06.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gatti M, Pattarozzi A, Bajetto A, Wurth R, Daga A, Fiaschi P, Zona G, Florio T, Barbieri F (2013) Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity. Toxicology 314(2-3):209–220. https://doi.org/10.1016/j.tox.2013.10.003

    Article  CAS  PubMed  Google Scholar 

  61. Gerber HP, Ferrara N (2005) Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 65(3):671–680

    CAS  PubMed  Google Scholar 

  62. Gerhardt H, Semb H (2008) Pericytes: gatekeepers in tumour cell metastasis? J Mol Med (Berl) 86(2):135–144. https://doi.org/10.1007/s00109-007-0258-2

    Article  Google Scholar 

  63. Ghajar CM (2015) Metastasis prevention by targeting the dormant niche. Nat Rev Cancer 15(4):238–247. https://doi.org/10.1038/nrc3910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, Almeida D, Koller A, Hajjar KA, Stainier DY, Chen EI, Lyden D, Bissell MJ (2013) The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 15(7):807–817. https://doi.org/10.1038/ncb2767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Giachino C, Boulay JL, Ivanek R, Alvarado A, Tostado C, Lugert S, Tchorz J, Coban M, Mariani L, Bettler B, Lathia J, Frank S, Pfister S, Kool M, Taylor V (2015) A tumor suppressor function for notch signaling in forebrain tumor subtypes. Cancer Cell 28(6):730–742. https://doi.org/10.1016/j.ccell.2015.10.008

    Article  CAS  PubMed  Google Scholar 

  66. Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, Mariani P, Andre F, Chan A, Lipatov O, Chan S, Wardley A, Greil R, Moore N, Prot S, Pallaud C, Semiglazov V (2013) AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol 31(14):1719–1725. https://doi.org/10.1200/JCO.2012.44.7912

    Article  CAS  PubMed  Google Scholar 

  67. Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13(12):871–882. https://doi.org/10.1038/nrc3627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Goel HL, Pursell B, Chang C, Shaw LM, Mao J, Simin K, Kumar P, Vander Kooi CW, Shultz LD, Greiner DL, Norum JH, Toftgard R, Kuperwasser C, Mercurio AM (2013) GLI1 regulates a novel neuropilin-2/alpha6beta1 integrin based autocrine pathway that contributes to breast cancer initiation. EMBO Mol Med 5(4):488–508. https://doi.org/10.1002/emmm.201202078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Greenblatt M, Shubi P (1968) Tumor angiogenesis: transfilter diffusion studies in the hamster by the transparent chamber technique. J Natl Cancer Inst 41(1):111–124

    CAS  PubMed  Google Scholar 

  70. Greene HS (1941) Heterologous transplantation of mammalian tumors: I. The Transfer of rabbit tumors to alien species. J Exp Med 73(4):461–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Guerin E, Man S, Xu P, Kerbel RS (2013) A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs. Cancer Res 73(9):2743–2748. https://doi.org/10.1158/0008-5472.CAN-12-4183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1(2):149–153

    Article  CAS  PubMed  Google Scholar 

  75. Hurvitz SA, Perez EA, Yamamoto H, Valero V, O’Neill V, Rugo HS (2012) Final overall survival (OS) and safety analyses of RIBBON-2, a randomized phase III trial of bevacizumab (BEV) versus placebo (PL) combined with second-line chemotherapy (CT) for HER2-negative BEV-naive metastatic breast cancer (MBC). J Clin Oncol 30(27_suppl):100

    Article  Google Scholar 

  76. Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmuller G, Klein CA (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13(1):58–68. https://doi.org/10.1016/j.ccr.2007.12.003

    Article  CAS  PubMed  Google Scholar 

  77. Ide AG, Baker NH, Warren SL (1939) Vascularization of the Brown-Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am J Roentgenol 42:891–899

    Google Scholar 

  78. Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD, McDonald DM (2004) Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 165(1):35–52. https://doi.org/10.1016/S0002-9440(10)63273-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Jedeszko C, Paez-Ribes M, Di Desidero T, Man S, Lee CR, Xu P, Bjarnason GA, Bocci G, Kerbel RS (2015) Postsurgical adjuvant or metastatic renal cell carcinoma therapy models reveal potent antitumor activity of metronomic oral topotecan with pazopanib. Sci Transl Med 7(282):282ra250. https://doi.org/10.1126/scitranslmed.3010722

    Article  CAS  Google Scholar 

  80. Jimenez-Valerio G, Martinez-Lozano M, Bassani N, Vidal A, Ochoa-de-Olza M, Suarez C, Garcia-Del-Muro X, Carles J, Vinals F, Graupera M, Indraccolo S, Casanovas O (2016) Resistance to antiangiogenic therapies by metabolic symbiosis in renal cell carcinoma PDX models and patients. Cell Rep 15(6):1134–1143. https://doi.org/10.1016/j.celrep.2016.04.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22(11):2184–2191. https://doi.org/10.1200/JCO.2004.11.022

    Article  CAS  PubMed  Google Scholar 

  82. Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, Miletic H, Wang J, Stieber D, Stuhr L, Moen I, Rygh CB, Bjerkvig R, Niclou SP (2011) Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci U S A 108(9):3749–3754. https://doi.org/10.1073/pnas.1014480108

    Article  PubMed  PubMed Central  Google Scholar 

  83. Kienast Y, Klein C, Scheuer W, Raemsch R, Lorenzon E, Bernicke D, Herting F, Yu S, The HH, Martarello L, Gassner C, Stubenrauch KG, Munro K, Augustin HG, Thomas M (2013) Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin Cancer Res 19(24):6730–6740. https://doi.org/10.1158/1078-0432.CCR-13-0081

    Article  CAS  PubMed  Google Scholar 

  84. Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert WE, Goldbrunner R, Herms J, Winkler F (2010) Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 16(1):116–122. https://doi.org/10.1038/nm.2072

    Article  CAS  PubMed  Google Scholar 

  85. Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C, Wilber A, Watabe K (2011) Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med 208(13):2641–2655. https://doi.org/10.1084/jem.20110840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lathia JD, Li M, Hall PE, Gallagher J, Hale JS, Wu Q, Venere M, Levy E, Rani MR, Huang P, Bae E, Selfridge J, Cheng L, Guvenc H, McLendon RE, Nakano I, Sloan AE, Phillips HS, Lai A, Gladson CL, Bredel M, Bao S, Hjelmeland AB, Rich JN (2012) Laminin alpha 2 enables glioblastoma stem cell growth. Ann Neurol 72(5):766–778. https://doi.org/10.1002/ana.23674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, Zhou A, Eyob H, Balakrishnan S, Wang CY, Yaswen P, Goga A, Werb Z (2015) Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 526(7571):131–135. https://doi.org/10.1038/nature15260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S, Ferrara N, Nagy A, Roos KP, Iruela-Arispe ML (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell 130(4):691–703. https://doi.org/10.1016/j.cell.2007.06.054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935):1306–1309

    Article  CAS  PubMed  Google Scholar 

  90. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, Group SIS (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390. https://doi.org/10.1056/NEJMoa0708857

    Article  CAS  PubMed  Google Scholar 

  91. Lu J, Ye X, Fan F, Xia L, Bhattacharya R, Bellister S, Tozzi F, Sceusi E, Zhou Y, Tachibana I, Maru DM, Hawke DH, Rak J, Mani SA, Zweidler-McKay P, Ellis LM (2013) Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23(2):171–185. https://doi.org/10.1016/j.ccr.2012.12.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M, Yan J, Hua Y, Tiede BJ, Lu X, Haffty BG, Pantel K, Massague J, Kang Y (2011) VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell 20(6):701–714. https://doi.org/10.1016/j.ccr.2011.11.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Malladi S, Macalinao DG, Jin X, He L, Basnet H, Zou Y, de Stanchina E, Massague J (2016) Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165(1):45–60. https://doi.org/10.1016/j.cell.2016.02.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715. https://doi.org/10.1016/j.cell.2008.03.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Marches R, Scheuermann R, Uhr J (2006) Cancer dormancy: from mice to man. Cell Cycle 5(16):1772–1778

    Article  CAS  PubMed  Google Scholar 

  96. Martin M, Loibl S, von Minckwitz G, Morales S, Martinez N, Guerrero A, Anton A, Aktas B, Schoenegg W, Munoz M, Garcia-Saenz JA, Gil M, Ramos M, Margeli M, Carrasco E, Liedtke C, Wachsmann G, Mehta K, De la Haba-Rodriguez JR (2015) Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study. J Clin Oncol 33(9):1045–1052. https://doi.org/10.1200/JCO.2014.57.2388

    Article  CAS  PubMed  Google Scholar 

  97. Martin M, Roche H, Pinter T, Crown J, Kennedy MJ, Provencher L, Priou F, Eiermann W, Adrover E, Lang I, Ramos M, Latreille J, Jagiello-Gruszfeld A, Pienkowski T, Alba E, Snyder R, Almel S, Rolski J, Munoz M, Moroose R, Hurvitz S, Banos A, Adewoye H, Hei YJ, Lindsay MA, Rupin M, Cabaribere D, Lemmerick Y, Mackey JR, T Investigators (2011) Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol 12(4):369–376. https://doi.org/10.1016/S1470-2045(11)70037-7

    Article  CAS  PubMed  Google Scholar 

  98. Marui N, Offermann MK, Swerlick R, Kunsch C, Rosen CA, Ahmad M, Alexander RW, Medford RM (1993) Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest 92(4):1866–1874. https://doi.org/10.1172/JCI116778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Mazzone M, Dettori D, de Oliveira RL, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, de Almodovar CR, De Smet F, Vinckier S, Aragones J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P (2009) Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136(5):839–851. https://doi.org/10.1016/j.cell.2009.01.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LW, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10(24):8152–8162. https://doi.org/10.1158/1078-0432.CCR-04-1110

    Article  PubMed  Google Scholar 

  101. Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O’Shaughnessy J (2017a) Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer 70:146–155. https://doi.org/10.1016/j.ejca.2016.09.024

    Article  CAS  PubMed  Google Scholar 

  102. Miles D, Cameron D, Hilton M, Garcia J, O’Shaughnessy J (2017b) Overall survival in MERiDiAN, a double-blind placebo-controlled randomised phase III trial evaluating first-line bevacizumab plus paclitaxel for HER2-negative metastatic breast cancer. Eur J Cancer 90:153–155. https://doi.org/10.1016/j.ejca.2017.10.018

    Article  CAS  PubMed  Google Scholar 

  103. Miles DW, Chan A, Dirix LY, Cortes J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G (2010) Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28(20):3239–3247. https://doi.org/10.1200/JCO.2008.21.6457

    Article  CAS  PubMed  Google Scholar 

  104. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–2676. https://doi.org/10.1056/NEJMoa072113

    Article  CAS  PubMed  Google Scholar 

  105. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23(4):792–799. https://doi.org/10.1200/JCO.2005.05.098

    Article  CAS  PubMed  Google Scholar 

  106. Mittal K, Williams A, Rawal S, Venur VA, Lu B, Torres-Munoz J, Borden EC, Ao Z, OMalley M, Wood LS, Zheng S, Datar RH, Tai YC, Cote RJ, Rini BI (2014) Circulating tumor cell kinetics in mRCC patients treated with sunitinib. J Clin Oncol 32(4). https://doi.org/10.1200/jco.2014.32.4_suppl.481

    Article  Google Scholar 

  107. Mountzios G, Pentheroudakis G, Carmeliet P (2014) Bevacizumab and micrometastases: revisiting the preclinical and clinical rollercoaster. Pharmacol Ther 141(2):117–124. https://doi.org/10.1016/j.pharmthera.2013.09.003

    Article  CAS  PubMed  Google Scholar 

  108. Nahleh ZA, Barlow WE, Hayes DF, Schott AF, Gralow JR, Sikov WM, Perez EA, Chennuru S, Mirshahidi HR, Corso SW, Lew DL, Pusztai L, Livingston RB, Hortobagyi GN (2016) SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer. Breast Cancer Res Treat 158(3):485–495. https://doi.org/10.1007/s10549-016-3889-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Naume B, Synnestvedt M, Falk RS, Wiedswang G, Weyde K, Risberg T, Kersten C, Mjaaland I, Vindi L, Sommer HH, Satersdal AB, Rypdal MC, Bendigtsen Schirmer C, Wist EA, Borgen E (2014) Clinical outcome with correlation to disseminated tumor cell (DTC) status after DTC-guided secondary adjuvant treatment with docetaxel in early breast cancer. J Clin Oncol 32(34):3848–3857

    Article  PubMed  Google Scholar 

  110. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15(3):220–231. https://doi.org/10.1016/j.ccr.2009.01.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Paez-Ribes M, Man S, Xu P, Kerbel RS (2015) Potential proinvasive or metastatic effects of preclinical antiangiogenic therapy are prevented by concurrent chemotherapy. Clin Cancer Res 21(24):5488–5498. https://doi.org/10.1158/1078-0432.CCR-15-0915

    Article  CAS  PubMed  Google Scholar 

  112. Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G, Funke I, Izbicki JR, Riethmuller G (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 85(17):1419–1424

    Article  CAS  PubMed  Google Scholar 

  113. Park JS, Kim IK, Han S, Park I, Kim C, Bae J, Oh SJ, Lee S, Kim JH, Woo DC, He Y, Augustin HG, Kim I, Lee D, Koh GY (2016) Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell 30(6):953–967. https://doi.org/10.1016/j.ccell.2016.10.018

    Article  CAS  PubMed  Google Scholar 

  114. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3(4):347–361

    Article  PubMed  Google Scholar 

  115. Pezzella F, Di Bacco A, Viale G, Nicholson AG, Price R, Ratcliffe C, Pastorino U, Gatter KC, Altman DG, Harris AL, Pilotti S, Veronesi U (2000) Evidence for novel non-angiogenic pathway in breast-cancer metastasis. Breast cancer progression working party. Lancet 355(9217):1787–1788

    Article  Google Scholar 

  116. Phillips RJ, Burdick MD, Lutz M, Belperio JA, Keane MP, Strieter RM (2003) The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med 167(12):1676–1686. https://doi.org/10.1164/rccm.200301-071OC

    Article  PubMed  Google Scholar 

  117. Pisarsky L, Bill R, Fagiani E, Dimeloe S, Goosen RW, Hagmann J, Hess C, Christofori G (2016) Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep 15(6):1161–1174. https://doi.org/10.1016/j.celrep.2016.04.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Pitt LA, Tikhonova AN, Hu H, Trimarchi T, King B, Gong Y, Sanchez-Martin M, Tsirigos A, Littman DR, Ferrando AA, Morrison SJ, Fooksman DR, Aifantis I, Schwab SR (2015) CXCL12-producing vascular endothelial niches control acute T cell leukemia maintenance. Cancer Cell 27(6):755–768. https://doi.org/10.1016/j.ccell.2015.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Pivot X, Schneeweiss A, Verma S, Thomssen C, Passos-Coelho JL, Benedetti G, Ciruelos E, von Moos R, Chang HT, Duenne AA, Miles DW (2011) Efficacy and safety of bevacizumab in combination with docetaxel for the first-line treatment of elderly patients with locally recurrent or metastatic breast cancer: results from AVADO. Eur J Cancer 47(16):2387–2395. https://doi.org/10.1016/j.ejca.2011.06.018

    Article  CAS  PubMed  Google Scholar 

  120. Price TT, Burness ML, Sivan A, Warner MJ, Cheng R, Lee CH, Olivere L, Comatas K, Magnani J, Kim Lyerly H, Cheng Q, McCall CM, Sipkins DA (2016) Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci Transl Med 8(340):340ra373. https://doi.org/10.1126/scitranslmed.aad4059

    Article  Google Scholar 

  121. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21(3):418–429. https://doi.org/10.1016/j.ccr.2012.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355):222–225. https://doi.org/10.1038/nature10138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Rafii S, Butler JM, Ding BS (2016) Angiocrine functions of organ-specific endothelial cells. Nature 529(7586):316–325. https://doi.org/10.1038/nature17040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, Nishigaki I (2013) The vascular endothelium and human diseases. Int J Biol Sci 9(10):1057–1069. https://doi.org/10.7150/ijbs.7502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, Fan AC, Yang Q, Braunstein L, Crosby E, Ryeom S, Felsher DW (2010) CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 18(5):485–498. https://doi.org/10.1016/j.ccr.2010.10.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Martini JF, Ramaswamy K, Casey M, Staehler M, Patard JJ, ST Investigators (2016) Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 375(23):2246–2254. https://doi.org/10.1056/NEJMoa1611406

    Article  CAS  PubMed  Google Scholar 

  127. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Horsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364(6):501–513. https://doi.org/10.1056/NEJMoa1003825

    Article  CAS  PubMed  Google Scholar 

  128. Relf M, LeJeune S, Scott PA, Fox S, Smith K, Leek R, Moghaddam A, Whitehouse R, Bicknell R, Harris AL (1997) Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57(5):963–969

    CAS  PubMed  Google Scholar 

  129. Robert NJ, Dieras V, Glaspy J, Brufsky A, Bondarenko I, Lipatov O, Perez E, Yardley D, Zhou X, Phan S (2009) RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 27(15_suppl):1005

    Google Scholar 

  130. Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SYT, Zhou X, Phan S-C, O’Shaughnessy J (2011a) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29(10):1252–1260

    Article  CAS  PubMed  Google Scholar 

  131. Robert NJ, Saleh MN, Paul D, Generali D, Gressot L, Copur MS, Brufsky AM, Minton SE, Giguere JK, Smith JW 2nd, Richards PD, Gernhardt D, Huang X, Liau KF, Kern KA, Davis J (2011b) Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin Breast Cancer 11(2):82–92. https://doi.org/10.1016/j.clbc.2011.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Russell WE, McGowan JA, Bucher NL (1984) Partial characterization of a hepatocyte growth factor from rat platelets. J Cell Physiol 119(2):183–192. https://doi.org/10.1002/jcp.1041190207

    Article  CAS  PubMed  Google Scholar 

  133. Sanger N, Effenberger KE, Riethdorf S, Van Haasteren V, Gauwerky J, Wiegratz I, Strebhardt K, Kaufmann M, Pantel K (2011) Disseminated tumor cells in the bone marrow of patients with ductal carcinoma in situ. Int J Cancer 129(10):2522–2526. https://doi.org/10.1002/ijc.25895

    Article  CAS  PubMed  Google Scholar 

  134. Schwartzberg LS, Tauer KW, Hermann RC, Makari-Judson G, Isaacs C, Beck JT, Kaklamani V, Stepanski EJ, Rugo HS, Wang W, Bell-McGuinn K, Kirshner JJ, Eisenberg P, Emanuelson R, Keaton M, Levine E, Medgyesy DC, Qamar R, Starr A, Ro SK, Lokker NA, Hudis CA (2013) Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab. Clin Cancer Res 19(10):2745–2754. https://doi.org/10.1158/1078-0432.CCR-12-3177

    Article  CAS  PubMed  Google Scholar 

  135. Seaman S, Zhu Z, Saha S, Zhang XM, Yang MY, Hilton MB, Morris K, Szot C, Morris H, Swing DA, Tessarollo L, Smith SW, Degrado S, Borkin D, Jain N, Scheiermann J, Feng Y, Wang Y, Li J, Welsch D, DeCrescenzo G, Chaudhary A, Zudaire E, Klarmann KD, Keller JR, Dimitrov DS, St Croix B (2017) Eradication of tumors through simultaneous ablation of CD276/B7-H3-positive tumor cells and tumor vasculature. Cancer Cell 31(4):501–515 e508. https://doi.org/10.1016/j.ccell.2017.03.005

    Article  PubMed  PubMed Central  Google Scholar 

  136. Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DT, McDonald DM (2012) Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2(3):270–287. https://doi.org/10.1158/2159-8290.CD-11-0240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N (2007a) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25(8):911–920. https://doi.org/10.1038/nbt1323

    Article  CAS  PubMed  Google Scholar 

  138. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard D, Bais C, Peale FV, van Bruggen N, Ho C, Ross J, Tan M, Carano RA, Meng YG, Ferrara N (2007b) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450(7171):825–831. https://doi.org/10.1038/nature06348

    Article  CAS  PubMed  Google Scholar 

  139. Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP (2015) Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33(1):13–21. https://doi.org/10.1200/JCO.2014.57.0572

    Article  CAS  PubMed  Google Scholar 

  140. Sosa MS, Bragado P, Aguirre-Ghiso JA (2014) Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 14(9):611–622. https://doi.org/10.1038/nrc3793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Sounni NE, Cimino J, Blacher S, Primac I, Truong A, Mazzucchelli G, Paye A, Calligaris D, Debois D, De Tullio P, Mari B, De Pauw E, Noel A (2014) Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab 20(2):280–294. https://doi.org/10.1016/j.cmet.2014.05.022

    Article  CAS  PubMed  Google Scholar 

  142. Spiliotaki M, Mavroudis D, Kapranou K, Markomanolaki H, Kallergi G, Koinis F, Kalbakis K, Georgoulias V, Agelaki S (2014) Evaluation of proliferation and apoptosis markers in circulating tumor cells of women with early breast cancer who are candidates for tumor dormancy. Breast Cancer Res 16(6):485. https://doi.org/10.1186/s13058-014-0485-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Srivastava K, Hu J, Korn C, Savant S, Teichert M, Kapel SS, Jugold M, Besemfelder E, Thomas M, Pasparakis M, Augustin HG (2014) Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 26(6):880–895. https://doi.org/10.1016/j.ccell.2014.11.005

    Article  CAS  PubMed  Google Scholar 

  144. Stawowczyk M, Wellenstein MD, Lee SB, Yomtoubian S, Durrans A, Choi H, Narula N, Altorki NK, Gao D, Mittal V (2017) Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor. Neoplasia (New York, N Y ) 19(2):55–64

    Article  CAS  Google Scholar 

  145. Sweeney CJ, Chiorean EG, Verschraegen CF, Lee FC, Jones S, Royce M, Tye L, Liau KF, Bello A, Chao R, Burris HA (2010) A phase I study of sunitinib plus capecitabine in patients with advanced solid tumors. J Clin Oncol 28(29):4513–4520. https://doi.org/10.1200/JCO.2009.26.9696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Thorban S, Roder JD, Nekarda H, Funk A, Pantel K, Siewert JR (1996) Disseminated epithelial tumor cells in bone marrow of patients with esophageal cancer: detection and prognostic significance. World J Surg 20(5):567–572; discussion 572–563

    Article  CAS  PubMed  Google Scholar 

  147. Tian L, Goldstein A, Wang H, Ching Lo H, Sun Kim I, Welte T, Sheng K, Dobrolecki LE, Zhang X, Putluri N, Phung TL, Mani SA, Stossi F, Sreekumar A, Mancini MA, Decker WK, Zong C, Lewis MT, Zhang XH (2017) Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544(7649):250–254. https://doi.org/10.1038/nature21724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. van der Bilt JD, Kranenburg O, Nijkamp MW, Smakman N, Veenendaal LM, Te Velde EA, Voest EE, van Diest PJ, Borel Rinkes IH (2005) Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model. Hepatology 42(1):165–175. https://doi.org/10.1002/hep.20739

    Article  CAS  PubMed  Google Scholar 

  149. van der Veldt AA, Vroling L, de Haas RR, Koolwijk P, van den Eertwegh AJ, Haanen JB, van Hinsbergh VW, Broxterman HJ, Boven E (2012) Sunitinib-induced changes in circulating endothelial cell-related proteins in patients with metastatic renal cell cancer. Int J Cancer 131(4):E484–E493. https://doi.org/10.1002/ijc.26456

    Article  CAS  PubMed  Google Scholar 

  150. Vessella RL, Pantel K, Mohla S (2007) Tumor cell dormancy: an NCI workshop report. Cancer Biol Ther 6(9):1496–1504

    Article  PubMed  Google Scholar 

  151. von Minckwitz G, Loibl S, Untch M, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Gerber B, GA-Bs groups (2014a) Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)dagger. Ann Oncol 25(12):2363–2372. https://doi.org/10.1093/annonc/mdu455

    Article  Google Scholar 

  152. von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J (2014b) Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. The Lancet Oncol 15(11):1269–1278. https://doi.org/10.1016/S1470-2045(14)70439-5

    Article  CAS  Google Scholar 

  153. Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Levy C, Brain E, Pivot X, Putzu C, Gonzalez Martin A, de Ducla S, Easton V, von Minckwitz G (2016) Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol 27(11):2046–2052. https://doi.org/10.1093/annonc/mdw316

    Article  CAS  PubMed  Google Scholar 

  154. Wang H, Fu W, Im JH, Zhou Z, Santoro SA, Iyer V, DiPersio CM, Yu QC, Quaranta V, Al-Mehdi A, Muschel RJ (2004) Tumor cell alpha3beta1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis. J Cell Biol 164(6):935–941. https://doi.org/10.1083/jcb.200309112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Weis S, Cui J, Barnes L, Cheresh D (2004) Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol 167(2):223–229. https://doi.org/10.1083/jcb.200408130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wertheimer T, Velardi E, Tsai J, Cooper K, Xiao S, Kloss CC, Ottmuller KJ, Mokhtari Z, Brede C, deRoos P, Kinsella S, Palikuqi B, Ginsberg M, Young LF, Kreines F, Lieberman SR, Lazrak A, Guo P, Malard F, Smith OM, Shono Y, Jenq RR, Hanash AM, Nolan DJ, Butler JM, Beilhack A, Manley NR, Rafii S, Dudakov JA, van den Brink MRM (2018) Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration. Sci Immunol 3(19). https://doi.org/10.1126/sciimmunol.aal2736

    Article  PubMed  PubMed Central  Google Scholar 

  157. Wiedswang G, Borgen E, Karesen R, Kvalheim G, Nesland JM, Qvist H, Schlichting E, Sauer T, Janbu J, Harbitz T, Naume B (2003) Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol 21(18):3469–3478. https://doi.org/10.1200/JCO.2003.02.009

    Article  CAS  PubMed  Google Scholar 

  158. Wong AL, Sundar R, Wang TT, Ng TC, Zhang B, Tan SH, Soh TI, Pang AS, Tan CS, Ow SG, Wang L, Mogro J, Ho J, Jeyasekharan AD, Huang Y, Thng CH, Chan CW, Hartman M, Iau P, Buhari SA, Goh BC, Lee SC (2016) Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer. Oncotarget 7(39):64089–64099. https://doi.org/10.18632/oncotarget.11596

    Article  PubMed  PubMed Central  Google Scholar 

  159. Xian X, Hakansson J, Stahlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116(3):642–651. https://doi.org/10.1172/JCI25705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Yang Y, Zhang Y, Iwamoto H, Hosaka K, Seki T, Andersson P, Lim S, Fischer C, Nakamura M, Abe M, Cao R, Skov PV, Chen F, Chen X, Lu Y, Nie G, Cao Y (2016) Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat Commun 7:12680. https://doi.org/10.1038/ncomms12680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Yumoto K, Eber MR, Wang J, Cackowski FC, Decker AM, Lee E, Nobre AR, Aguirre-Ghiso JA, Jung Y, Taichman RS (2016) Axl is required for TGF-beta2-induced dormancy of prostate cancer cells in the bone marrow. Sci Rep 6:36520. https://doi.org/10.1038/srep36520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zhu TS, Costello MA, Talsma CE, Flack CG, Crowley JG, Hamm LL, He X, Hervey-Jumper SL, Heth JA, Muraszko KM, DiMeco F, Vescovi AL, Fan X (2011) Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res 71(18):6061–6072. https://doi.org/10.1158/0008-5472.CAN-10-4269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. Candice Grzelak for providing feedback on the manuscript. L.P. is funded by the Swiss National Science Foundation (Postdoc.Mobility Fellowships 165389 and 177917). The Ghajar Laboratory is funded by the U.S. Department of Defense Breast Cancer Research Program (BCRP; W841XWH-15-1-0201), a Physical Sciences Oncology Project Grant from the NIH/NCI (U54CA193461-01), the Keck Foundation, and the Breast Cancer Research Foundation.

Author information

Authors and Affiliations

  1. Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Laura Pisarsky & Cyrus M. Ghajar

Authors
  1. Laura Pisarsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cyrus M. Ghajar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Laura Pisarsky or Cyrus M. Ghajar .

Editor information

Editors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Julio A. Aguirre-Ghiso

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Pisarsky, L., Ghajar, C.M. (2018). Anti-angiogenic Therapy-Mediated Endothelial Damage: A Driver of Breast Cancer Recurrence?. In: Aguirre-Ghiso, J. (eds) Biological Mechanisms of Minimal Residual Disease and Systemic Cancer. Advances in Experimental Medicine and Biology, vol 1100. Springer, Cham. https://doi.org/10.1007/978-3-319-97746-1_2

Download citation

Publish with us

Policies and ethics

Search

Navigation