Top

Published in:

01-01-2008 | Preclinical Study/Clinical Trial/Epidemiology/Invited Commentary

Circulating endothelial progenitor cells correlate to stage in patients with invasive breast cancer

Authors: Rakhi P. Naik, David Jin, Ellen Chuang, Ellen G. Gold, Eleni A. Tousimis, Anne L. Moore, Paul J. Christos, Tatiana de Dalmas, Diana Donovan, Shahin Rafii, Linda T. Vahdat

Published in: Breast Cancer Research and Treatment | Issue 1/2008

Abstract

Tumor growth and metastasis is dependent on the formation and assembly of new blood vessels, a process known as neo-angiogenesis. Both pre-existing and circulating vascular cells have been shown to contribute to the assembly of tumor neo-vessels in specific tumors. Mobilization of endothelial progenitor cells (EPCs) from the bone marrow constitutes a crucial step in the formation of de novo blood vessels, and levels of peripheral blood EPCs have been shown to be increased in certain malignant states. However, the role of circulating EPCs in breast cancer is largely unknown. We recruited twenty-five patients with biopsy-proven invasive breast cancer at Weill Cornell Breast Center to participate in a pilot study investigating the correlation of circulating EPCs to extent of disease and initiation of chemotherapy. For each patient, a baseline sample was drawn before systemic treatment, and for seventeen of those patients, a second sample was taken after the first round of chemotherapy. Levels of peripheral blood EPCs, as defined by co-expression of CD133 and VEGFR2, were quantified by flow cytometry. Breast cancer patients with stage III & IV disease had statistically higher levels of circulating EPCs than did patients with stage I & II disease (median = 165,000 EPCs/5 × 10⁶MNCs vs. median = 6,920 EPCs/5 × 10⁶MNCs, respectively, P < 0.0001). In addition, in late-stage patients, levels of EPCs demonstrated a statistically significant drop after initiation of chemotherapy (median = 162,500 EPCs/5 × 10⁶MNCs [pre] vs. median = 117,500 EPCs/5 × 10⁶MNCs [post], P = 0.01). These results suggest that circulating EPCs may serve as a potential tumor biomarker in breast cancer and that EPCs may represent a plausible target for future therapeutic intervention.

Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49(23):6449–6465PubMed

Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1(1):27–31PubMedCrossRef

Folkman J (1995) Seminars in medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 333(26):1757–1763PubMedCrossRef

Rafii S (2000) Circulating endothelial precursor cells, mystery, reality and promise. J Clin Invest 105:17–19PubMedCrossRef

Stoll BR, Migliorini C, Kadambi A, Munn LL, Jain RK (2003) A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for antiangiogenic therapy. Blood 102(7):2555–2561PubMedCrossRef

Vajkoczy P, Blum S, Lamparter M, Mailhammer R, Erber R, Engelhardt B et al (2003) Multistep nature of microvascular recruitment of ex vivo-expanded embryonic endothelial progenitor cells during tumor angiogenesis. J Exp Med 197(12):1755–1765PubMedCrossRef

Lyden D, Hattori K, Dias S, Witte L, Hackett N, Crystal R et al (2001) Impaired recruitment of bone marrow derived endothelial and a hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201PubMedCrossRef

Peichev M, Naiyer A, Hicklin D, Witte L, Rafii S (2000) Expression of AC133 and VEFGR-2(KDR) by human CD34+ cells identifies a population of endothelial precursor cells. Blood 95:952–958PubMed

Gehling UM, Ergun S, Schumacher U, Wagener C, Pantel K, Otte M et al (2000) In vitro differentiation of endothelial cells from AC133-positive progenitor cells. Blood 95(10):3106–3112PubMed

10.

Quirici N, Soligo D, Caneva L, Servida F, Bossolasco P, Deliliers GL (2001) Differentiation and expansion of endothelial cells from human bone marrow CD133(+) cells. Br J Haematol 115(1):186–194PubMedCrossRef

11.

Furstenberger G, Moos Rv, Lucas R, Thurlimann B, Senn H, Hamacher J et al (2006) Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer. Br J Cancer 94:524–531PubMedCrossRef

12.

Zhang H, Vakil V, Braunstein M, Smith EL, Maroney J, Chen L et al (2005) Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood 105(8):3286–3294PubMedCrossRef

13.

Massa M, Rosti V, Ramajoli I, Campanelli R, Pecci A, Viarengo G et al (2005) Circulating CD34+, CD133+, and vascular endothelial growth factor receptor 2-positive endothelial progenitor cells in myelofibrosis with myeloid metaplasia. J Clin Oncol 23(24):5688–5695PubMedCrossRef

14.

Dome B, Timar J, Dobos J, Meszaros L, Raso E, Paku S et al (2006) Identification and clinical significance of circulating endothelial progenitor cells in human non-small cell lung cancer. Cancer Res 66(14):7341–7347PubMedCrossRef

15.

Friedrich EB, Walenta K, Scharlau J, Nickenig G, Werner N (2006) CD34-/CD133+/VEGFR-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities. Circ Res 98(3):e20–e25PubMedCrossRef

16.

Numaguchi Y, Sone T, Okumura K, Ishii M, Morita Y, Kubota R et al (2006) The impact of the capability of circulating progenitor cell to differentiate on myocardial salvage in patients with primary acute myocardial infarction. Circulation 114(1 Suppl):I114–I119PubMed

17.

Singletary SE, Allred C, Ashley P, Bassett LW, Berry D, Bland KI et al (2002) Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20(17):3628–3636PubMedCrossRef

18.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216PubMedCrossRef

19.

Bertolini F, Thomas T, Battaglia M, Gibelli N, Pedrazzoli P, Robustelli della Cuna G (1997) A new ‘two-step’ procedure for 4.5 log depletion of T and B cells in allogeneic transplantation and of neoplastic cells in autologous transplantation. Bone Marrow Transplant 19:615–619PubMedCrossRef

20.

Munoz R, Shaked Y, Bertolini F, Emmenegger U, Man S, Kerbel RS (2005) Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy. Breast 14(6):466–479PubMedCrossRef

21.

Gill M, Dias S, Hattori K, Lane W, Rivera L, Hicklin D et al (2001) Vascular trauma induces rapid but transient mobiliation of VEGFR2+AC133+ endothelial precursor cells. Circ Res 88:167–174PubMed

22.

Kong D, Melo LG, Gnecchi M, Zhang L, Mostoslavsky G, Liew CC et al (2004) Cytokine-induced mobilization of circulating endothelial progenitor cells enhances repair of injured arteries. Circulation 110(14):2039–2046PubMedCrossRef

23.

Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A et al (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353(10):999–1007PubMedCrossRef

24.

Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351(27):2817–2826PubMedCrossRef

25.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342PubMedCrossRef

26.

Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL et al (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349(5):427–434PubMedCrossRef

27.

Miller KD, Trigo JM, Wheeler C, Barge A, Rowbottom J, Sledge G et al (2005) A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 11(9):3369–3376PubMedCrossRef

28.

Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM et al (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):2184–2191PubMedCrossRef

29.

Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF et al (2003) A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 30(5 Suppl 16):117–124PubMedCrossRef

30.

Heymach J (2005) ZD 6474-clinical experience to date. Br J Cancer 92(Suppl 1):S14–S20PubMedCrossRef

31.

Gingrich DE, Reddy DR, Iqbal MA, Singh J, Aimone LD, Angeles TS et al (2003) A new class of potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: structure-activity relationships for a series of 9-alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5- ones and the identification of CEP-5214 and its dimethylglycine ester prodrug clinical candidate CEP-7055. J Med Chem 46(25):5375–5388PubMedCrossRef

32.

Ruggeri B, Singh J, Gingrich D, Angeles T, Albom M, Yang S et al (2003) CEP-7055: a novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models. Cancer Res 63(18):5978–5991PubMed

33.

Emanuel S, Gruninger RH, Fuentes-Pesquera A, Connolly PJ, Seamon JA, Hazel S et al (2004) A vascular endothelial growth factor receptor-2 kinase inhibitor potentiates the activity of the conventional chemotherapeutic agents paclitaxel and doxorubicin in tumor xenograft models. Mol Pharmacol 66(3):635–647PubMedCrossRef

Title: Circulating endothelial progenitor cells correlate to stage in patients with invasive breast cancer
Authors: Rakhi P. Naik
David Jin
Ellen Chuang
Ellen G. Gold
Eleni A. Tousimis
Anne L. Moore
Paul J. Christos
Tatiana de Dalmas
Diana Donovan
Shahin Rafii
Linda T. Vahdat
Publication date: 01-01-2008
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2008
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-007-9519-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2008

Activation of protein kinase A (PKA) signaling mitigates the antiproliferative and antiinvasive effects of α-difluoromethylornithine in breast cancer cells

BARD1 and breast cancer in Poland

Dietary animal-derived iron and fat intake and breast cancer risk in the Shanghai Breast Cancer Study

TGFβ2 and TβRII are valid molecular biomarkers for the antiproliferative effects of tamoxifen and tamoxifen metabolites in breast cancer cells

Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study

Quantitative detection of circulating epithelial cells by Q-RT-PCR

Keynote webinar | Spotlight on antibody–drug conjugates in cancer