Hostname: page-component-cd9895bd7-lnqnp Total loading time: 0 Render date: 2024-12-27T08:35:27.189Z Has data issue: false hasContentIssue false
  • English
  • Français

Hematopoietic Derived Cell Infiltration of the Intestinal Tumor Microenvironment in ApcMin/+ Mice

Published online by Cambridge University Press:  08 April 2011

Celestia Davis ,
Robert Price ,
Grishma Acharya ,
Troy Baudino ,
Thomas Borg ,
Franklin G. Berger  and
Maria Marjorette O. Peña
Celestia Davis
Affiliation:
Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
Robert Price
Affiliation:
Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA Department of Cell and Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
Grishma Acharya
Affiliation:
Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
Troy Baudino
Affiliation:
Department of Cell and Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
Thomas Borg
Affiliation:
Department of Cell and Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
Franklin G. Berger
Affiliation:
Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA
Maria Marjorette O. Peña*
Affiliation:
Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA
*
Corresponding author. E-mail: mpena@biol.sc.edu
Get access

Abstract

Tumors consist of a heterogeneous population of neoplastic cells infiltrated by an equally heterogeneous collection of nonneoplastic cells that comprise the tumor microenvironment. Tumor growth, invasion, and metastasis depend on multiple interactions between these cells. To assess their potential as therapeutic targets or vehicles for tumor specific delivery of therapeutic agents, we examined the contribution of bone marrow derived cells (BMDCs) to the intestinal tumor microenvironment. Hematopoietic stem cells expressing the enhanced green fluorescent protein (eGFP) were transplanted into lethally irradiated ApcMin/+ mice, and their engraftment was analyzed by confocal microscopy. The results showed abundant infiltration of eGFP cells into the small intestine, colon, and spleen compared to heart, muscle, liver, lung, and kidney. Within the intestine, there was a pronounced gradient of engraftment along the anterior to posterior axis, with enhanced infiltration into adenomas. Immunofluorescence analysis showed that osteopontin was expressed in tumor stromal cells but not in nontumor stromal populations, suggesting that gene expression in these cells is distinct. Tumor vasculature in ApcMin/+ mice was chaotic compared to normal intestinal regions. Our data suggest that BMDCs can be harnessed for tumor-targeted therapies to enhance antitumor efficacy.

Keywords

tumor microenvironmenthematopoietic stem cellsbone marrow derived cellscolon cancerApcMin/+ mice
Type
Cover Article
Information
Microscopy and Microanalysis , Volume 17 , Issue 4 , August 2011 , pp. 528 - 539
Copyright
Copyright © Microscopy Society of America 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

American Cancer Society (2009). Colorectal Cancer Facts and Figures 2008–2010. Atlanta, GA: American Cancer Society.Google Scholar
Berger, S.H., Davis, S.T., Barbour, K.W. & Berger, F.G. (1988). The role of thymidylate synthase in the response to fluoropyrimidine-folinic acid combinations. Adv Exp Med Biol 244, 59–69.CrossRefGoogle ScholarPubMed
Chantrain, C.F., Feron, O., Marbaix, E. & Declerck, Y.A. (2008). Bone marrow microenvironment and tumor progression. Cancer Microenviron 1, 23–35.CrossRefGoogle ScholarPubMed
Chau, I. & Cunningham, D. (2006). Adjuvant therapy in colon cancer—What, when and how? Ann Oncol 17, 1347–1359.CrossRefGoogle Scholar
Chen, L.C., Hao, C.Y., Chiu, Y.S., Wong, P., Melnick, J.S., Brotman, M., Moretto, J., Mendes, F., Smith, A.P., Bennington, J.L., Moore, D. & Lee, N.M. (2004). Alteration of gene expression in normal-appearing colon mucosa of APC(min) mice and human cancer patients. Cancer Res 64, 3694–3700.CrossRefGoogle ScholarPubMed
Coussens, L.M. & Werb, Z. (2001). Inflammatory cells and cancer: Think different! J Exp Med 193, F23–F26.CrossRefGoogle ScholarPubMed
Coussens, L.M. & Werb, Z. (2002). Inflammation and cancer. Nature 420, 860–867.CrossRefGoogle ScholarPubMed
Danenberg, P.V. (1977). Thymidylate synthetase—A target enzyme in cancer chemotherapy. Biochim Biophys Acta 473, 73–92.Google ScholarPubMed
Denhardt, D.T. & Noda, M. (1998). Osteopontin expression and function: Role in bone remodeling. J Cell Biochem Suppl 30–31, 92–102.3.0.CO;2-A>CrossRefGoogle ScholarPubMed
Denhardt, D.T., Noda, M., O'Regan, A.W., Pavlin, D. & Berman, J.S. (2001). Osteopontin as a means to cope with environmental insults: Regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 107, 1055–1061.CrossRefGoogle Scholar
Erdman, S.E., Rao, V.P., Poutahidis, T., Ihrig, M.M., Ge, Z., Feng, Y., Tomczak, M., Rogers, A.B., Horwitz, B.H. & Fox, J.G. (2003). CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res 63, 6042–6050.Google ScholarPubMed
Erdman, S.E., Sohn, J.J., Rao, V.P., Nambiar, P.R., Ge, Z., Fox, J.G. & Schauer, D.B. (2005). CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res 65, 3998–4004.CrossRefGoogle ScholarPubMed
Federsppiel, B., Melhado, I.G., Duncan, A.M., Delaney, A., Schappert, K., Clark-Lewis, I. & Jirik, F.R. (1993). Molecular cloning of the cDNA and chromosomal localization of the gene for a putative seven-transmembrane segment (7-TMS) receptor isolated from human spleen. Genomics 16, 707–712.CrossRefGoogle ScholarPubMed
Ferrari, N., Glod, J., Lee, J., Kobiler, D. & Fine, H.A. (2003). Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors. Gene Ther 10, 647–656.CrossRefGoogle ScholarPubMed
Fodde, R., Kuipers, J., Rosenberg, C., Smits, R., Kielman, M., Gaspar, C., Van Es, J.H., Breukel, C., Wiegant, J., Giles, R.H. & Clevers, H. (2001). Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 3, 433–438.CrossRefGoogle ScholarPubMed
Fuseler, J.W., Bedenbaugh, A., Yekkala, K. & Baudino, T.A. (2010). Fractal and image analysis of the microvasculature in normal intestinal submucosa and intestinal polyps in Apc(Min/+) mice. Microsc Microanal 16, 73–79.CrossRefGoogle ScholarPubMed
Gallagher, P.G., Bao, Y., Prorock, A., Zigrino, P., Nischt, R., Politi, V., Mauch, C., Dragulev, B. & Fox, J.W. (2005). Gene expression profiling reveals cross-talk between melanoma and fibroblasts: Implications for host-tumor interactions in metastasis. Cancer Res 65, 4134–4146.CrossRefGoogle ScholarPubMed
Galli, S.J., Nakae, S. & Tsai, M. (2005). Mast cells in the development of adaptive immune responses. Nat Immunol 6, 135–42.CrossRefGoogle ScholarPubMed
Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pages, C., Tosolini, M., Camus, M., Berger, A., Wind, P., Zinzindohoue, F., Bruneval, P., Cugnenc, P.H., Trajanoski, Z., Fridman, W.H. & Pages, F. (2006). Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964.CrossRefGoogle ScholarPubMed
Gounaris, E., Blatner, N.R., Dennis, K., Magnusson, F., Gurish, M.F., Strom, T.B., Beckhove, P., Gounari, F. & Khazaie, K. (2009). T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res 69, 5490–5497.CrossRefGoogle ScholarPubMed
Gounaris, E., Erdman, S.E., Restaino, C., Gurish, M.F., Friend, D.S., Gounari, F., Lee, D.M., Zhang, G., Glickman, J.N., Shin, K., Rao, V.P., Poutahidis, T., Weissleder, R., McNagny, K.M. & Khazaie, K. (2007). Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci USA 104, 19977–19982.CrossRefGoogle ScholarPubMed
Hall, B.M., Fortney, J.E., Taylor, L., Wood, H., Wang, L., Adams, S., Davis, S. & Gibson, L.F. (2004). Stromal cells expressing elevated VCAM-1 enhance survival of B lineage tumor cells. Cancer Lett 207, 229–239.CrossRefGoogle ScholarPubMed
Hanna, E., Quick, J. & Libutti, S.K. (2009). The tumour microenvironment: A novel target for cancer therapy. Oral Dis 15, 8–17.CrossRefGoogle ScholarPubMed
Hofmeister, V., Schrama, D. & Becker, J.C. (2008). Anti-cancer therapies targeting the tumor stroma. Cancer Immunol Immunother 57, 1–17.CrossRefGoogle ScholarPubMed
Jenq, R.R. & van den Brink, M.R. (2010). Allogeneic haematopoietic stem cell transplantation: Individualized stem cell and immune therapy of cancer. Nat Rev Cancer 10, 213–221.CrossRefGoogle ScholarPubMed
Jin, D.K., Shido, K., Kopp, H.G., Petit, I., Shmelkov, S.V., Young, L.M., Hooper, A.T., Amano, H., Avecilla, S.T., Heissig, B., Hattori, K., Zhang, F., Hicklin, D.J., Wu, Y., Zhu, Z., Dunn, A., Salari, H., Werb, Z., Hackett, N.R., Crystal, R.G., Lyden, D. & Rafii, S. (2006). Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nat Med 12, 557–567.CrossRefGoogle ScholarPubMed
Kettunen, H.L., Kettunen, A.S. & Rautonen, N.E. (2003). Intestinal immune responses in wild-type and Apcmin/+ mouse, a model for colon cancer. Cancer Res 63, 5136–5142.Google Scholar
Kinzler, K.W. & Vogelstein, B. (1996). Lessons from hereditary colorectal cancer. Cell 87, 159–170.CrossRefGoogle ScholarPubMed
Kitahara, O., Furukawa, Y., Tanaka, T., Kihara, C., Ono, K., Yanagawa, R., Nita, M.E., Takagi, T., Nakamura, Y. & Tsunoda, T. (2001). Alterations of gene expression during colorectal carcinogenesis revealed by cDNA microarrays after laser-capture microdissection of tumor tissues and normal epithelia. Cancer Res 61, 3544–3549.Google ScholarPubMed
Lin, E.Y., Nguyen, A.V., Russell, R.G. & Pollard, J.W. (2001). Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193, 727–740.CrossRefGoogle ScholarPubMed
Littlepage, L.E., Egeblad, M. & Werb, Z. (2005). Coevolution of cancer and stromal cellular responses. Cancer Cell 7, 499–500.CrossRefGoogle ScholarPubMed
Longley, D.B., Harkin, D.P. & Johnston, P.G. (2003). 5-Fluorouracil: Mechanisms of action and clinical strategies. Nat Rev Cancer 3, 330–338.CrossRefGoogle ScholarPubMed
Masuya, M., Drake, C.J., Fleming, P.A., Reilly, C.M., Zeng, H., Hill, W.D., Martin-Studdard, A., Hess, D.C. & Ogawa, M. (2003). Hematopoietic origin of glomerular mesangial cells. Blood 101, 2215–2218.CrossRefGoogle ScholarPubMed
Moser, A.R., Dove, W.F., Roth, K.A. & Gordon, J.I. (1992). The Min (multiple intestinal neoplasia) mutation: Its effect on gut epithelial cell differentiation and interaction with a modifier system. J Cell Biol 116, 1517–1526.CrossRefGoogle ScholarPubMed
Moser, A.R., Pitot, H.C. & Dove, W.F. (1990). A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322–324.CrossRefGoogle ScholarPubMed
Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M.E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S.N., Barrera, J.L., Mohar, A., Verastegui, E. & Zlotnik, A. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56.CrossRefGoogle ScholarPubMed
Nicolella, D., Maione, P. & Gridelli, C. (2003). Targeted therapies: Focus on a new strategy for gastrointestinal tumors. Crit Rev Oncol Hematol 47, 261–271.CrossRefGoogle ScholarPubMed
Obermueller, E., Vosseler, S., Fusenig, N.E. & Mueller, M.M. (2004). Cooperative autocrine and paracrine functions of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the progression of skin carcinoma cells. Cancer Res 64, 7801–7812.CrossRefGoogle ScholarPubMed
Orimo, A. & Weinberg, R.A. (2006). Stromal fibroblasts in cancer: A novel tumor-promoting cell type. Cell Cycle 5, 1597–1601.CrossRefGoogle Scholar
Papaspyridonos, M. & Lyden, D. (2008). Chapter 11. The role of bone marrow-derived cells in tumor angiogenesis and metastatic progression. Methods Enzymol 444, 255–269.CrossRefGoogle ScholarPubMed
Pietras, K., Rubin, K., Sjoblom, T., Buchdunger, E., Sjoquist, M., Heldin, C.H. & Ostman, A. (2002). Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res 62, 5476–5484.Google ScholarPubMed
Purhonen, S., Palm, J., Rossi, D., Kaskenpaa, N., Rajantie, I., Yla-Herttuala, S., Alitalo, K., Weissman, I.L. & Salven, P. (2008). Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci USA 105, 6620–6625.CrossRefGoogle Scholar
Rafii, S., Lyden, D., Benezra, R., Hattori, K. & Heissig, B. (2002). Vascular and haematopoietic stem cells: Novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2, 826–835.CrossRefGoogle ScholarPubMed
Rizvi, A.Z., Swain, J.R., Davies, P.S., Bailey, A.S., Decker, A.D., Willenbring, H., Grompe, M., Fleming, W.H. & Wong, M.H. (2006). Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc Natl Acad Sci USA 103, 6321–6325.CrossRefGoogle ScholarPubMed
Roorda, B.D., Ter Elst, A., Kamps, W.A. & De Bont, E.S. (2009). Bone marrow-derived cells and tumor growth: Contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells. Crit Rev Oncol Hematol 69, 187–198.CrossRefGoogle ScholarPubMed
Salvucci, O., Basik, M., Yao, L., Bianchi, R. & Tosato, G. (2004). Evidence for the involvement of SDF-1 and CXCR4 in the disruption of endothelial cell-branching morphogenesis and angiogenesis by TNF-alpha and IFN-gamma. J Leukoc Biol 76, 217–226.CrossRefGoogle ScholarPubMed
Schwarz, Y.X., Yang, M., Qin, D., Wu, J., Jarvis, W.D., Grant, S., Burton, G.F., Szakal, A.K. & Tew, J.G. (1999). Follicular dendritic cells protect malignant B cells from apoptosis induced by anti-Fas and antineoplastic agents. J Immunol 163, 6442–6447.CrossRefGoogle ScholarPubMed
Shoemaker, A.R., Gould, K.A., Luongo, C., Moser, A.R. & Dove, W.F. (1997). Studies of neoplasia in the Min mouse. Biochim Biophys Acta 1332, F25–F48.Google ScholarPubMed
Sugiyama, Y., Farrow, B., Murillo, C., Li, J., Watanabe, H., Sugiyama, K. & Evers, B.M. (2005). Analysis of differential gene expression patterns in colon cancer and cancer stroma using microdissected tissues. Gastroenterology 128, 480–486.CrossRefGoogle ScholarPubMed
Vincent, J., Mignot, G., Chalmin, F., Ladoire, S., Bruchard, M., Chevriaux, A., Martin, F., Apetoh, L., Rebe, C. & Ghiringhelli, F. (2010). 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 70, 3052–3061.CrossRefGoogle ScholarPubMed
Wang, L., Chen, L., Benincosa, J., Fortney, J. & Gibson, L.F. (2005). VEGF-induced phosphorylation of Bcl-2 influences B lineage leukemic cell response to apoptotic stimuli. Leukemia 19, 344–353.CrossRefGoogle ScholarPubMed
Wang, L., Fortney, J.E. & Gibson, L.F. (2004). Stromal cell protection of B-lineage acute lymphoblastic leukemic cells during chemotherapy requires active Akt. Leuk Res 28, 733–742.CrossRefGoogle ScholarPubMed
Weaver, V.M., Lelievre, S., Lakins, J.N., Chrenek, M.A., Jones, J.C., Giancotti, F., Werb, Z. & Bissell, M.J. (2002). Beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2, 205–216.CrossRefGoogle ScholarPubMed
Yang, L., Huang, J., Ren, X., Gorska, A.E., Chytil, A., Aakre, M., Carbone, D.P., Matrisian, L.M., Richmond, A., Lin, P.C. & Moses, H.L. (2008). Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13, 23–35.CrossRefGoogle ScholarPubMed
Supplementary material: PDF

Davis et al. Supplementary Material

Davis et al. Supplementary Figures

Download Davis et al. Supplementary Material(PDF)
PDF 183 KB