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Cancer Stem Cells and Metastasis: Emerging Themes and Therapeutic Implications

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Stem Cells and Cancer

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Abstract

Recent work in the field of cancer research has provided mounting evidence for the role of cancer stem cells in the establishment of many types of tumors. Insights into intrinsic properties of cancer stem cells are especially important in the context of tumor invasion and metastasis. Although more research is still necessary to solidify the role of cancer stem cells in the initiation of metastatic growth, the multistep cascade of tumor growth and progression as it is currently understood encompasses events likely to involve cancer stem cells and the microenvironment that supports them. This chapter will focus on the perceived roles of cancer stem cells in known tumorigenic and metastatic events. Emerging and evolving models of cancer stem cell-mediated tumor progression provide potential windows of opportunity for developing novel therapeutic strategies aiming at thwarting the menacing power of metastatic cancer stem cells.

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References

  • Abraham, B., Fritz, P., McClellan, M., et al. 2005. Prevalence of CD44+/CS24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clinical Cancer Research 11: 1154–1159.

    PubMed  CAS  Google Scholar 

  • Adams, G., Chabner, K., Alley, I., et al. 2006. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439: 599–603.

    Article  PubMed  CAS  Google Scholar 

  • Al-Hajj, M., Wicha, M., Benito-Hernandez, A., Morrison, S., and Clarke, M. 2003. Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Science USA 100: 3983–3988.

    Article  CAS  Google Scholar 

  • Bachoo, R., Maher, E., Ligon, K., Sharpless, N., Chan, S., et al. 2002. Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1: 269–277.

    Article  PubMed  CAS  Google Scholar 

  • Balic, M., Lin, H., Young, L., et al. 2006. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clinical Cancer Research 12: 5615–5621.

    Article  PubMed  CAS  Google Scholar 

  • Bao, S., Wu, Q., McLendon, R., Hao, Y., Shi, Q., et al. 2006a. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444: 756–760.

    Article  PubMed  CAS  Google Scholar 

  • Bao, S., Wu, Q., Sathornumetee, S., Hao, Y., Li, Z., et al. 2006b. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial factor. Cancer Research 66: 7843–7848.

    Article  PubMed  CAS  Google Scholar 

  • Barnhart, B. and Simon, M. 2007. Metastasis and stem cell pathways. Cancer Metastasis Review 26: 261–271.

    Article  CAS  Google Scholar 

  • Bernards, R. and Weinberg, R.A. 2002. A progression puzzle. Nature 418 (6900): 823.

    Article  PubMed  CAS  Google Scholar 

  • Brabletz, T., Jung, A., Reu, S., et al. 2001. Variable B-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Science USA 98: 10356–10361.

    Article  CAS  Google Scholar 

  • Cairns, J. 2002. Somatic stem cells and the kinetics of mutagenesis and carcinogenesis. Proceedings of the National Academy of Science USA 99: 10567–10570.

    Article  CAS  Google Scholar 

  • Calvi, L., Adams, G., Weibrecht, K., et al. 2003. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425: 841–846.

    Article  PubMed  CAS  Google Scholar 

  • Chambers, A.F., Groom, A.C., and MacDonald, I.C. 2002. Dissemination and growth of cancer cells in metastatic sites. Nature Reviews 2 (8): 563–572.

    Article  PubMed  CAS  Google Scholar 

  • Chen, L., Shen, R., Ye, Y., Pu, X., Liu, X., et al. 2007. Precancerous stem cells have the potential for both benign and malignant differentiation. PLoS ONE 22: e293.

    Article  Google Scholar 

  • Desai, K., Xiao, N., Wang, W., Gangi, L., Greene, J., et al. 2002. Initiating oncogenic event determines gene-expression patterns of human breast cancer models. Proceedings of the National Academy of Science USA 99: 6967–6972.

    Article  CAS  Google Scholar 

  • Eriksson, M., Guse, K., Bauerschmitz, G., Virkkunen, P., Tarkkanen, M., et al. 2007. Oncolytic adenoviruses kill breast cancer initiating CD44(+)CD24(-/low) cells. Molecular Therapy 12: 2060–2061.

    Google Scholar 

  • Fidler, I. and Talmadge, J. 1986. Evidence that intravenously derived murine pulmonary melanoma metastases can originate from the expansion of a single tumor cell. Cancer Research 46: 5167–5171.

    PubMed  CAS  Google Scholar 

  • Furger, K., Menon, R., Tuck, A., Bramwell, V., and Chambers, A. 2001. The functional and clinical roles of osteopontin in cancer and metastasis. Current Molecular Medicine 1: 621–632.

    Article  PubMed  CAS  Google Scholar 

  • Gotzmann, J., Fischer, A.N.M., Zojer, M., Mikula, M., Proell, V., Huber, H., Jechlinger, M., Waerner, T., Weith, A., Beug, H., and Mikulits, W. 2006. A crucial function of PDGF in TGF-B-mediated cancer progression of hepatocytes. Oncogene 25: 3170–3185.

    Article  PubMed  CAS  Google Scholar 

  • Guise, T., Mohammad, K., Clines, G., Stebbins, E., Wong, D., et al. 2006. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clinical Cancer Research 12: 6213s–6216s.

    Article  Google Scholar 

  • Gupta, G. and Massague, J. 2006. Cancer metastasis: building a framework. Cell 127: 679–695.

    Article  PubMed  CAS  Google Scholar 

  • Hanahan, D. and Weinberg, R. 2000. The hallmarks of cancer. Cell 100: 57–70.

    Article  PubMed  CAS  Google Scholar 

  • Hermann, P., Huber, S., Herrier, T., Aicher, A., Ellwart, J., et al. 2007. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1: 313–323.

    Article  PubMed  CAS  Google Scholar 

  • Hermann, P., Huber, S., and Heeschen, C. 2008. Metastatic cancer stem cells: a new target for anti-cancer therapy? Cell Cycle 7: 188–193.

    Article  PubMed  CAS  Google Scholar 

  • Hiratsuka, S., Watanabe, A., Aburatani, J., and Maru, Y. 2006. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nature Cell Biology 8: 1369–1375.

    Article  PubMed  CAS  Google Scholar 

  • Ho, M., Ng, A., Lam, S., and Hung, J. 2007. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Research 67: 4827–4833.

    Article  PubMed  CAS  Google Scholar 

  • Hu, G., Chong, R.A., Yang, Q., Wei, Y., Blanco, M.A., Li, F., Reiss, M., Au, J.L., Haffy, B., and Kang, Y. 2009. MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell 15: 9–20.

    Google Scholar 

  • Hurwitz, J., Fehrenbacher, L., Novonty, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., Ferrara, N., Fyfe, G., Rogers, B., Ross, R., and Kabbinavar, F. 2004. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England Journal of Medicine 350: 2335–2342.

    Article  PubMed  CAS  Google Scholar 

  • Hynes, R. 2003. Metastatic potential: generic predisposition of the primary tumor or rare, metastatic variants—or both? Cell 113: 821–823.

    Article  PubMed  CAS  Google Scholar 

  • Ince, T., Richardson, A., Bell, G., Saitoh, M., Godar, S., et al. 2007. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 12: 160–170.

    Article  PubMed  CAS  Google Scholar 

  • Ito, M., Yang, Z., Andl, T., Cui, C., Kim, N., et al. 2007. Wnt-dependant de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447: 316–320.

    Article  PubMed  CAS  Google Scholar 

  • Jain, R. 2001. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nature Medicine 7: 987–989.

    Article  PubMed  CAS  Google Scholar 

  • Jamieson, C., Ailles, L., Dylla, S., Muijtjens, M., Jones, C., et al. 2004. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. New England Journal of Medicine 351: 657–667.

    Article  PubMed  CAS  Google Scholar 

  • Jemal, A., Siegel, R., Ward, W., Murray, T., Xu, J., et al. 2007. Cancer statistics, 2007. CA Cancer Journal of Clinicians 57: 43–66.

    Article  Google Scholar 

  • Jin, L., Hope, K., Zhai, Q., Smadja-Joffe, F., and Dick, J. 2006. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nature Medicine 12: 1167–1174.

    Article  PubMed  Google Scholar 

  • Kang, Y. 2005. Functional genomic analysis of cancer metastasis: biologic insights and clinical implications. Expert Review of Molecular Diagnostics 5 (3): 385–395.

    Article  PubMed  CAS  Google Scholar 

  • Kang, Y., Siegel, R., Shu, W., Drobnjak, M., Kakonen, S., et al. 2003. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3: 537–549.

    Article  PubMed  CAS  Google Scholar 

  • Kaplan, R., Riba, R., Zacharoulis, S., Bramley, A., Vincent, L., et al. 2005. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438: 820–827.

    Article  PubMed  CAS  Google Scholar 

  • Kim, C., Kackson, E., Woolfenden, A., et al. 2005. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121: 823–835.

    Article  PubMed  CAS  Google Scholar 

  • Kollet, O., Dar, A., Shivtiel, S., Kalinkovixh, A., Lapid, K., et al. 2006. Osteoclasts degrade endosteal components and promote mobilizations of hematopoietic progenitor cells. Nature Medicine 12: 657–664.

    Article  PubMed  CAS  Google Scholar 

  • Krause, D., Lazarides, K., van Andrian, U., and van Etten, R. 2006. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nature Medicine 12: 1175–1180.

    Article  PubMed  CAS  Google Scholar 

  • Krivtsov, A., Twomey, D., Feng, Z., Stubbs, M., Wang, Y., et al. 2006. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442: 821–822.

    Article  Google Scholar 

  • Li, L. and Neaves, W. 2006. Normal stem cells and cancer stem cells: the niche matters. Cancer Research 66: 4553–4557.

    Article  PubMed  CAS  Google Scholar 

  • Li, F., Tiede, B., Massague, J., and Kang, Y. 2006. Beyond tumorigenesis: cancer stem cells in metastasis. Cell Research 17: 3–14.

    Article  Google Scholar 

  • Lin, M. and Sessa, W. 2004. Antiangiogenic therapy: creating a unique "window" of opportunity. Cancer Cell 6: 529–531.

    PubMed  CAS  Google Scholar 

  • Ma, S., Lee, T., Zheng, B., Chan, K., and Guan, X. 2008. CD133(+) HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27: 1749–1758.

    Article  PubMed  CAS  Google Scholar 

  • Mihai, R., Stevens, J., McKinney, C., and Ibrahim, N.B. 2006. Expression of the calcium receptor in human breast cancer—a potential new marker predicting the risk of bone metastases. European Journal of Surgical Oncology 32 (5): 511–515.

    Article  PubMed  CAS  Google Scholar 

  • Minn, A.J., Gupta, G.P., Siegel, P.M., et al. 2005a. Genes that mediate breast cancer metastasis to lung. Nature 436: 518–524.

    Article  PubMed  CAS  Google Scholar 

  • Minn, A.J., Kang, Y., Serganova, I., Gupta, G.P., Giri, D., Doubrovin, M., Ponomarev, V., Gerald, W., Blasberg, R., and Massague, J. 2005b. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. The Journal of Clinical Investigation 115: 44–55.

    PubMed  CAS  Google Scholar 

  • Miyamoto, T., Weissman, I., and Akashi, K. 2000. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8:21 chromosomal translocation. Proceedings of the National Academy of Science USA 97: 7521–7526.

    Article  CAS  Google Scholar 

  • 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., and Zlotnik, A. 2001. Involvement of chemokine receptors in breast cancer metastasis. Nature 410 (6824): 50–56.

    Article  PubMed  CAS  Google Scholar 

  • Paget, S. 1989. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Reviews 8 (2): 98–101.

    PubMed  CAS  Google Scholar 

  • Perou, C., Jeffrey, S., Van De Rinj, M., Rees, C., Wisen, M., et al. 1999. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proceedings of the National Academy of Science USA 2002: 9212–9217.

    Article  Google Scholar 

  • Phillips, T., McBride, W., and Pajonk, F. 2006. The response of CD24(-/low)/CD44+ breast cancer initiating cells to radiation. Journal of the National Cancer Institute 98: 1777–1785.

    Article  PubMed  Google Scholar 

  • Piccirillo, S., Reynolds, B., Zanetti, N., et al. 2006. Bone morphogenic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444: 761–765.

    Article  PubMed  CAS  Google Scholar 

  • Ramaswamy, S., Ross, K., Lander, E., and Golub, T. 2003. A molecular signature of metastasis in primary solid tumors. Nature Genetics 33: 49–54.

    Article  PubMed  CAS  Google Scholar 

  • Scadden, D. 2006. The stem-cell niche as an entity of action. Nature 441: 1075–1079.

    Article  PubMed  CAS  Google Scholar 

  • Scheel, C., Onder, T., Karnoub, A., and Weinberg, R. 2007. Adaptation versus selection: the origins of metastatic behavior. Cancer Research 67: 11476–11479.

    Article  PubMed  CAS  Google Scholar 

  • Schofield, R. 1978. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4: 7–25.

    PubMed  CAS  Google Scholar 

  • Shackelton, M., Vaillant, F., Simpson, K., Stingl, J., Smyth, G., et al. 2006. Generation of a functional mammary gland from a single stem cell. Nature 439: 84–88.

    Article  Google Scholar 

  • Sheridan, C., Kishimoto, H., Fuchs, R., Mehrotra, S., Bhat-Nakshatri, P., et al. 2006. CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Cancer Research 8: R59.

    Google Scholar 

  • Shipitsin, M., Campbell, L., Argani, P., Weremowicz, S., Bloushtain-Qimron, N., et al. 2007. Molecular definition of breast tumor heterogeneity. Cancer Cell 11: 259–273.

    Article  PubMed  CAS  Google Scholar 

  • Sleeman, J. and Cremers, N. 2007. New concepts in breast cancer metastasis: tumor initiating cells and the microenvironment. Clinical & Experimental Metastasis 24: 707–715.

    Article  CAS  Google Scholar 

  • Sneddon, J., Zhen, H., Montgomery, K., et al. 2006. Bone morphogenetic protein antagonist gremlin1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proceedings of the National Academy of Science USA 103: 14842–14847.

    Article  CAS  Google Scholar 

  • Sorlie, T., Perou, C., Tibshirani, R., Aas, T., Geisler, S., et al. 2001. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Science USA 98: 10869–10874.

    Article  CAS  Google Scholar 

  • Steeg, P.S. 2006. Tumor metastasis: mechanistic insights and clinical challenges. Nature Medicine 12 (8): 895–904.

    Article  PubMed  CAS  Google Scholar 

  • Stier, S., Ko, Y., Forkert, R., et al. 2005. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. Journal of Experimental Medicine 201: 1781–1791.

    Article  PubMed  CAS  Google Scholar 

  • Stingl, J. and Caldas, C. 2007. Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis. Nature Review Cancer 7: 791–799.

    Google Scholar 

  • Taichman, R.S., Cooper, C., Keller, E.T., Pienta, K.J., Taichman, N.S., and McCauley, L.K. 2002. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Research 62 (6): 1832–1837.

    PubMed  CAS  Google Scholar 

  • Tavor, S., Petit, I., Porozov, S., Avigdor, A., Dar, A., et al. 2004. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Research 64: 2817–2824.

    Article  PubMed  CAS  Google Scholar 

  • Turhan, A., Lemoine, F., Debert, C., Bonnet, M., Baillou, C., et al. 1995. Highly purified primitive hematopoietic stem cells are PML-RARA negative and generate nonclonal progenitors in acute promyelocytic leukemia. Blood 85: 2154–2161.

    PubMed  CAS  Google Scholar 

  • van de Vijver, M., He, Y., van't Veer, L., Dai, H., Hart, A., et al. 2002. A gene-expression signature as a predictor of survival in breast cancer. New England Journal of Medicine 347: 1999–2009.

    Article  PubMed  Google Scholar 

  • van't Veer, L., Dai, H., van de Vijver, M., He, Y., Hart, A., et al. 2002. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415: 530–536.

    Article  Google Scholar 

  • Vescovi, A., Galli, R., and Reynolds, B. 2006. Brain tumour stem cells. Nature Review Cancer 6: 425–436.

    Article  CAS  Google Scholar 

  • Wang, Y., Klijn, J., Zhang, Y., Sieuwerts, A., Look, M., et al. 2005. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365: 671–679.

    PubMed  CAS  Google Scholar 

  • Weigelt, B., Hu, Z., He, X., et al. 2005a. Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Research 65: 9155–9158.

    Article  PubMed  CAS  Google Scholar 

  • Weigelt, B., Peterse, J.L., and van 't Veer, L.J. 2005b. Breast cancer metastasis: markers and models. Nature Reviews Cancer 5 (8): 591–602.

    Article  PubMed  CAS  Google Scholar 

  • Wernig, M., Meissner, A., Foreman, R., et al. 2007. In vitro reprogramming of fibroblasts into pluripotent ES-cell-like state. Nature 448: 318–324.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA

    Leah Owens, Benjamin Tiede & Yibin Kang

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  1. Leah Owens
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  2. Benjamin Tiede
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  3. Yibin Kang
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Correspondence to Yibin Kang .

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    Owens, L., Tiede, B., Kang, Y. (2009). Cancer Stem Cells and Metastasis: Emerging Themes and Therapeutic Implications. In: Majumder, S. (eds) Stem Cells and Cancer. Springer, New York, NY. https://doi.org/10.1007/978-0-387-89611-3_4

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