Abstract
Patients and animals bearing tumors have increased levels of CD34+ progenitor cells, which are capable of developing into dendritic cells. However, addition of medium conditioned by murine Lewis lung carcinoma cells increases the cellularity of the CD34+ cell cultures and redirects their differentiation into endothelial cells. The resulting cells resemble endothelial cells phenotypically as well as functionally by their capacity to reorganize into cord structures. Mechanisms by which tumors induced the increased cellularity and skewing toward endothelial cells were examined. Tumor-derived VEGF contributed to the increase in cellularity, but not to the redirection of differentiation. Differentiation into endothelial cells was blocked with sTie-2, suggesting tumor-derived angiopoietins in skewing differentiation. These studies show the capacity of tumors to skew progenitor cell development toward endothelial cells and define the mediators that contribute to endothelial cell development.
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References
Achen MG, Stacker SA (1998) The vascular endothelial growth factor family; proteins which guide the development of the vasculature. Int J Exp Pathol 79:255–265
Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC (1997) The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 185:111–120
Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI (2001) Increased production of immature myeloid cells in cancer patients: A mechanism of immunosuppression in cancer. J Immunol 166:678–689
Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP, Gabrilovich DI (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6:1755–1766
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967
Banich JC, Kolesiak K, Young MR (2003) Chemoattraction of CD34+ progenitor cells and dendritic cells to the site of tumor excision as the first step of an immunotherapeutic approach to target residual tumor cells. J Immunother 26:31–40
Beck LJ, D’Amore PA (1997) Vascular development: cellular and molecular regulation. FASEB J 11:365–373
Dutt P, Wang JF, Groopman JE (1998) Stromal cell-derived factor-1 alpha and stem cell factor/kit ligand share signaling pathways in hemopoietic progenitors: a potential mechanism for cooperative induction of chemotaxis. J Immunol 161:3652–3658
Feraud O, Cao Y, Vittet D (2001) Embryonic stem cell-derived embryoid bodies development in collagen gels recapitulates sprouting angiogenesis. Lab Invest 81:1669–1681
Garrity T, Pandit R, Wright MA, Benefield J, Young MRI (1997) Increased presence of CD34+ cells in the peripheral blood of head and neck cancer patients and their differentiation into CD1a+ cells. Int J Cancer 73:663–669
Gupta RA, Tejada LV, Tong BJ, Das SK, Morrow JD, Dey SK, DuBois RN (2003) Cyclooxygenase-1 is overexpressed and promotes angiogenic growth factor production in ovarian cancer. Cancer Res 63:906–911
Hirashima M, Kataoka H, Nishikawa S, Matsuyoshi N (1999) Maturation of embryonic stem cells into endothelial cells in an in vitro model of vasculogenesis. Blood 93:1253–1263
Isner JM, Asahara T (1999) Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Invest 103:1231–1236
Kim CH, Broxmeyer HE (1998) In vitro behavior of hematopoietic progenitor cells under the influence of chemoattractants: stromal cell-derived factor-1, steel factor, and the bone marrow environment. Blood 91:100–110
Koga K, Todaka T, Morioka M, Hamada J, Kai Y, Yano S, Okamura A, Takakura N, Suda T, Ushio Y (2001) Expression of angiopoietin-2 in human glioma cells and its role for angiogenesis. Cancer Res 61:6248–6254
Lathers DM, Achille N, Young MR (2003) Dendritic cell development from mobilized peripheral blood CD34+ cells. Methods Mol Biol 215:409–415
Lathers DMR, Achille N, Kolesiak K, Hulett K, Sparano A, Young MRI (2001) Increased levels of immune inhibitory CD34+ progenitor cells in the peripheral blood of patients with node positive head and neck cancer and the ability of the CD34+ cells to differentiate into antigen presenting dendritic cells. Clin Cancer Res 125:205–212
Lathers DMR, Lubbers E, Wright MA, Young MRI (1999) Dendritic cell differentiation pathways of CD34+ cells from the peripheral blood of head and neck cancer patients. J Leukoc Biol 65:623–628
Melani C, Stoppacciaro A, Foroni C, Felicetti F, Care A, Colombo MP (2004) Angiopoietin decoy secreted at tumor site impairs tumor growth and metastases by inducing local inflammation and altering neoangiogenesis. Cancer Immunol Immunother 53:600–608
Schofield KP, Rushton G, Humphries MJ, Dexter TM, Gallagher JT (1997) Influence of interleukin-3 and other growth factors on α4β1 integrin-mediated adhesion and migration of human hematopoietic progenitor cells. Blood 90:1858–1866
Schuch G, Heymach JV, Nomi M, Machluf M, Force J, Atala A, Eder JP Jr, Folkman J, Soker S (2003) Endostatin inhibits the vascular endothelial growth factor-induced mobilization of endothelial progenitor cells. Cancer Res 63:8345–8350
Shirakawa K, Furuhata S, Watanabe I, Hayase H, Shimizu A, Ikarashi Y, Yoshida T, Terada M, Hashimoto D, Wakasugi H (2002) Induction of vasculogenesis in breast cancer models. Br J Cancer 87:1454–1461
Springer ML, Chen AS, Kraft PE, Bednarski M, Blau HM (1998) VEGF gene delivery to muscle: potential role for vasculogenesis in adults. Mol Cell 2:549–558
Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T (1999) Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5:434–438
Tanaka F, Ishikawa S, Yanagihara K, Miyahara R, Kawano Y, Li M, Otake Y, Wada H (2002) Expression of angiopoietins and its clinical significance in non-small cell lung cancer. Cancer Res 62:7124–7129
Tsuda S, Ohtsuru A, Yamashita S, Kanetake H, Kanda S (2002) Role of c-Fyn in FGF-2-mediated tube-like structure formation by murine brain capillary endothelial cells. Biochem Biophys Res Commun 290:1354–1360
Vinals F, Pouyssegur J (2001) Transforming growth factor β1 (TGF-β1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-α signaling. Mol Cell Biol 21:7218–7230
Young MR (2004) Tumor skewing of CD34+ progenitor cell differentiation into endothelial cells. Int J Cancer 109:516–524
Young MR, Kolesiak K, Wright MA, Gabrilovich DI (1999) Chemoattraction of femoral CD34+ progenitor cells by tumor-derived vascular endothelial cell growth factor. Clin Exp Metastasis 17:881–888
Young MR, Wright MA, Lathers DM, Messingham KA (1999) Increased resistance to apoptosis by bone marrow CD34+ progenitor cells from tumor-bearing mice. Int J Cancer 82:609–615
Young MR, Young ME, Kim K (1988) Regulation of tumor-induced myelopoiesis and the associated immune suppressor cells in mice bearing metastatic Lewis lung carcinomas by prostaglandin E2. Cancer Res 48:6826–6831
Young MRI, Halpin J, Wang J, Wright MA, Matthews J, Schmidt-Pak A (1993) 1α,25-dihydroxyvitamin D3 plus γ-interferon blocks lung tumor production of granulocyte-macrophage colony-stimulating factor and induction of immunosuppressor cells. Cancer Res 53:6006–6010
Young MRI, Petruzzelli G, Kolesiak K, Lathers DMR, Lingen MW, Gabrilovich D (2001) Human squamous cell carcinomas of the head and neck chemoattract immune suppressive CD34+ progenitor cells. Hum Immunol 62:332–341
Young MRI, Schmidt-Pak A, Wright MA, Matthews JP, Collins SL, Petruzzelli G (1995) Mechanisms of immune suppression in patients with head and neck cancer: Presence of immune suppressive CD34+ cells in cancers that secrete granulocyte-macrophage colony-stimulating factor. Clin Cancer Res 1:95–103
Young MRI, Wright MA (1992) Myelopoiesis-associated immune suppressor cells in mice bearing metastatic Lewis lung carcinoma tumors: interferon-γ plus tumor necrosis factor-α synergistically reduce immune suppressor and tumor growth-promoting activities of bone marrow cells, and diminish tumor recurrence and metastasis. Cancer Res 52:6335–6340
Young MRI, Wright MA, Lozano Y, Matthews JP, Benefield J, Prechel MM (1996) Mechanisms of immune suppression in patients with head and neck cancer: influence on the immune infiltrate of the cancer. Int J Cancer 67:333–338
Young MRI, Wright MA, Lozano Y, Prechel MM, Benefield J, Leonetti JP, Collins SL, Petruzzelli GJ (1997) Increased recurrence and metastasis in patients whose primary head and neck squamous cell carcinomas secreted granulocyte-macrophage colony-stimulating factor and contained CD34+ natural suppressor cells. Int J Cancer 74:69–74
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This work was supported by the Medical Research Service of the Department of Veterans Affairs, and by grants CA97813 and CA85266 from the National Institutes of Health (MRIY).
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Young, M.R.I., Cigal, M. Tumor skewing of CD34+ cell differentiation from a dendritic cell pathway into endothelial cells. Cancer Immunol Immunother 55, 558–568 (2006). https://doi.org/10.1007/s00262-005-0036-3
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DOI: https://doi.org/10.1007/s00262-005-0036-3