Mesenchymal stem cells and cancer: Friends or enemies?

Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis

Volumn 768, Issue C, 2014, Pages 98-106

  Hong, In Sun ^a   Lee, Hwa Yong ^b   Kang, Kyung Sun ^c  

^a Gachon University College of Medicine   (South Korea)

^b Jungwon University   (South Korea)

^c Seoul National University   (South Korea)

Author keywords

Gene therapy; Immune surveillance; Mesenchymal stem cells; Prodrug; Tropism; Tumor microenvironments

Indexed keywords

EID: 84894618283     PISSN: 00275107     EISSN: 18792871     Source Type: Journal    
DOI: 10.1016/j.mrfmmm.2014.01.006     Document Type: Review

References (130)

1. Bray F., Moller B. Predicting the future burden of cancer. Nat. Rev. Cancer 2006, 6(1):63-74.
2. Koontongkaew S. The tumor microenvironment contribution to development: growth, invasion and metastasis of head and neck squamous cell carcinomas. J. Cancer 2013, 4(1):66-83.
3. Zischek C., et al. Targeting tumor stroma using engineered mesenchymal stem cells reduces the growth of pancreatic carcinoma. Ann. Surg. 2009, 250(5):747-753.
4. Kidd S., et al. Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells 2009, 27(10):2614-2623.
5. Beckermann B.M., et al. VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br. J. Cancer 2008, 99(4):622-631.
6. Block G.J., et al. Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1. Stem Cells 2009, 27(3):670-681.
7. Nomoto-Kojima N., et al. Interaction between adipose tissue stromal cells and gastric cancer cells in vitro. Cell Tissue Res. 2011, 344(2):287-298.
8. Seo S.H., et al. The effects of mesenchymal stem cells injected via different routes on modified IL-12-mediated antitumor activity. Gene Ther. 2011, 18(5):488-495.
9. Friedenstein A.J., Chailakhjan R.K., Lalykina K.S. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 1970, 3(4):393-403.
10. Erices A., Conget P., Minguell J.J. Mesenchymal progenitor cells in human umbilical cord blood. Br. J. Haematol. 2000, 109(1):235-242.
11. Villaron E.M., et al. Mesenchymal stem cells are present in peripheral blood and can engraft after allogeneic hematopoietic stem cell transplantation. Haematologica 2004, 89(12):1421-1427.
12. Fukuchi Y., et al. Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells 2004, 22(5):649-658.
13. Zuk P.A., et al. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell 2002, 13(12):4279-4295.
14. Pevsner-Fischer M., Levin S., Zipori D. The origins of mesenchymal stromal cell heterogeneity. Stem Cell Rev. 2011, 7(3):560-568.
15. Dominici M., et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8(4):315-317.
16. Chamberlain G., et al. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 2007, 25(11):2739-2749.
17. Brooke G., et al. Therapeutic applications of mesenchymal stromal cells. Semin. Cell Dev. Biol. 2007, 18(6):846-858.
18. Stagg J., et al. Interferon-gamma-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell. Blood 2006, 107(6):2570-2577.
19. Jones B.J., McTaggart S.J. Immunosuppression by mesenchymal stromal cells: from culture to clinic. Exp. Hematol. 2008, 36(6):733-741.
20. Kim J.W., et al. Bone marrow derived mesenchymal stem cell transplantation for chronic spinal cord injury in rats: comparative study between intralesional and intravenous transplantation. Spine (Phila Pa 1976) 2013, 38:E1065-E1074.
21. Carvalho J.L., et al. Priming mesenchymal stem cells boosts stem cell therapy to treat myocardial infarction. J. Cell Mol. Med. 2013, 17(5):617-625.
22. Di Bella C., Farlie P., Penington A.J. Bone regeneration in a rabbit critical-sized skull defect using autologous adipose-derived cells. Tissue Eng. A 2008, 14(4):483-490.
23. Bulman S.E., et al. Enhancing the mesenchymal stem cell therapeutic response: cell localization and support for cartilage repair. Tissue Eng. B Rev. 2013, 19(1):58-68.
24. Cipriani P., et al. Mesenchymal stem cells (MSCs) from scleroderma patients (SSc) preserve their immunomodulatory properties although senescent and normally induce T regulatory cells (Tregs) with a functional phenotype: implications for cellular based therapy. Clin. Exp. Immunol. 2013, 173:195-206.
25. Kim N., et al. Mesenchymal stem cells for the treatment and prevention of graft-versus-host disease: experiments and practice. Ann. Hematol. 2013, 92:1295-1308.
26. Dvorak H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 1986, 315(26):1650-1659.
27. Loebinger M.R., et al. Magnetic resonance imaging of mesenchymal stem cells homing to pulmonary metastases using biocompatible magnetic nanoparticles. Cancer Res. 2009, 69(23):8862-8867.
28. Sasportas L.S., et al. Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proc. Natl. Acad. Sci. U. S. A. 2009, 106(12):4822-4827.
29. Patel S.A., et al. Mesenchymal stem cells protect breast cancer cells through regulatory T cells: role of mesenchymal stem cell-derived TGF-beta. J. Immunol. 2010, 184(10):5885-5894.
30. Menon L.G., et al. Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells. Stem Cells 2007, 25(2):520-528.
31. Studeny M., et al. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res. 2002, 62(13):3603-3608.
32. Sun L., Lee J., Fine H.A. Neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury. J. Clin. Invest. 2004, 113(9):1364-1374.
33. Magge S.N., et al. Role of monocyte chemoattractant protein-1 (MCP-1/CCL2) in migration of neural progenitor cells toward glial tumors. J. Neurosci. Res. 2009, 87(7):1547-1555.
34. Schmidt N.O., et al. Vascular endothelial growth factor-stimulated cerebral microvascular endothelial cells mediate the recruitment of neural stem cells to the neurovascular niche. Brain Res. 2009, 1268:24-37.
35. Garzotto D., et al. Hepatocyte growth factor regulates migration of olfactory interneuron precursors in the rostral migratory stream through Met-Grb2 coupling. J. Neurosci. 2008, 28(23):5901-5909.
36. Carbajal K.S., et al. Migration of engrafted neural stem cells is mediated by CXCL12 signaling through CXCR4 in a viral model of multiple sclerosis. Proc. Natl. Acad. Sci. U. S. A. 2010, 107(24):11068-11073.
37. Son B.R., et al. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 2006, 24(5):1254-1264.
38. Abarbanell A.M., et al. Proinflammatory cytokine effects on mesenchymal stem cell therapy for the ischemic heart. Ann. Thorac. Surg. 2009, 88(3):1036-1043.
39. Nakamizo A., et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 2005, 65(8):3307-3318.
40. Motaln H., Schichor C., Lah T.T. Human mesenchymal stem cells and their use in cell-based therapies. Cancer 2010, 116(11):2519-2530.
41. Dwyer R.M., et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin. Cancer Res. 2007, 13(17):5020-5027.
42. 34- progenitor cells functionally express the chemokine receptors CCR1: CCR4, CCR7, CXCR5, and CCR10 but not CXCR4. Stem Cells Dev. 2005, 14(3):329-336.
43. Shah K. Mesenchymal stem cells engineered for cancer therapy. Adv. Drug Deliv. Rev. 2012, 64(8):739-748.
44. Loebinger M.R., et al. Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res. 2009, 69(10):4134-4142.
45. Li H., Fan X., Houghton J. Tumor microenvironment: the role of the tumor stroma in cancer. J. Cell Biochem. 2007, 101(4):805-815.
46. Xu W.T., et al. Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis. Cancer Lett. 2009, 281(1):32-41.
47. Zhu W., et al. Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp. Mol. Pathol. 2006, 80(3):267-274.
48. Spaeth E.L., et al. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS ONE 2009, 4(4):e4992.
49. Okumura T., et al. Identification of a bone marrow-derived mesenchymal progenitor cell subset that can contribute to the gastric epithelium. Lab. Invest. 2009, 89(12):1410-1422.
50. Meisel R., et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004, 103(12):4619-4621.
51. Maby-El Hajjami H., et al. Functional alteration of the lymphoma stromal cell niche by the cytokine context: role of indoleamine-2,3 dioxygenase. Cancer Res. 2009, 69(7):3228-3237.
52. Uyttenhove C., et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 2003, 9(10):1269-1274.
53. Mazzoni A., et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J. Immunol. 2002, 168(2):689-695.
54. Sato K., et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 2007, 109(1):228-234.
55. Ren G., et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008, 2(2):141-150.
56. Aggarwal S., Pittenger M.F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005, 105(4):1815-1822.
57. Nemeth K., et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 2009, 15(1):42-49.
58. Spaggiari G.M., et al. MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 2009, 113(26):6576-6583.
59. Akira S., Taga T., Kishimoto T. Interleukin-6 in biology and medicine. Adv. Immunol. 1993, 54:1-78.
60. Hirano T., et al. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc. Natl. Acad. Sci. U. S. A. 1985, 82(16):5490-5494.
61. Uyttenhove C., Coulie P.G., Van Snick J. T cell growth and differentiation induced by interleukin-HP1/IL-6: the murine hybridoma/plasmacytoma growth factor. J. Exp. Med. 1988, 167(4):1417-1427.
62. Giraudo E., et al. IL-6 is an in vitro and in vivo autocrine growth factor for middle T antigen-transformed endothelial cells. J. Immunol. 1996, 157(6):2618-2623.
63. Djouad F., et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells 2007, 25(8):2025-2032.
64. Carmeliet P. Angiogenesis in life: disease and medicine. Nature 2005, 438(7070):932-936.
65. Zheng W., et al. Mechanisms of coronary angiogenesis in response to stretch: role of VEGF and TGF-beta. Am. J. Physiol. Heart Circ. Physiol. 2001, 280(2):H909-H917.
66. Feng B., Chen L. Review of mesenchymal stem cells and tumors: executioner or coconspirator?. Cancer Biother. Radiopharm. 2009, 24(6):717-721.
67. Wang Y., et al. TGF-alpha increases human mesenchymal stem cell-secreted VEGF by MEK- and PI3-K- but not JNK- or ERK-dependent mechanisms. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008, 295(4):R1115-R1123.
68. Lee D.C., et al. Transforming growth factor alpha: expression, regulation, and biological activities. Pharmacol. Rev. 1995, 47(1):51-85.
69. Silva G.V., et al. Mesenchymal stem cells differentiate into an endothelial phenotype: enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation 2005, 111(2):150-156.
70. Armulik A., Genove G., Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 2011, 21(2):193-215.
71. Rajantie I., et al. Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 2004, 104(7):2084-2086.
72. Al-Khaldi A., et al. Postnatal bone marrow stromal cells elicit a potent VEGF-dependent neoangiogenic response in vivo. Gene Ther. 2003, 10(8):621-629.
73. Kalluri R., Neilson E.G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 2003, 112(12):1776-1784.
74. Valdes F., et al. The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. Mol. Cancer Res. 2002, 1(1):68-78.
75. Klymkowsky M.W., Savagner P. Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. Am. J. Pathol. 2009, 174(5):1588-1593.
76. Polyak K., Weinberg R.A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 2009, 9(4):265-273.
77. Martin F.T., et al. Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT). Breast Cancer Res. Treat. 2010, 124(2):317-326.
78. Pietras K., Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res. 2010, 316(8):1324-1331.
79. Albini A., Sporn M.B. The tumour microenvironment as a target for chemoprevention. Nat. Rev. Cancer 2007, 7(2):139-147.
80. Hwang R.F., et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008, 68(3):918-926.
81. Giannoni E., et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res. 2010, 70(17):6945-6956.
82. Kalluri R., Zeisberg M. Fibroblasts in cancer. Nat. Rev. Cancer 2006, 6(5):392-401.
83. Simian M., et al. The interplay of matrix metalloproteinases: morphogens and growth factors is necessary for branching of mammary epithelial cells. Development 2001, 128(16):3117-3131.
84. Quante M., et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 2011, 19(2):257-272.
85. Ogawa M., LaRue A.C., Drake C.J. Hematopoietic origin of fibroblasts/myofibroblasts: its pathophysiologic implications. Blood 2006, 108(9):2893-2896.
86. Lu Y.R., et al. The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo. Cancer Biol. Ther. 2008, 7(2):245-251.
87. Secchiero P., et al. Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin's lymphoma xenografts. PLoS ONE 2010, 5(6):e11140.
88. Zhu Y., et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 2009, 23(5):925-933.
89. Dasari V.R., et al. Cord blood stem cell-mediated induction of apoptosis in glioma downregulates X-linked inhibitor of apoptosis protein (XIAP). PLoS ONE 2010, 5(7):e11813.
90. Papkoff J., Brown A.M., Varmus H.E. The int-1 proto-oncogene products are glycoproteins that appear to enter the secretory pathway. Mol. Cell Biol. 1987, 7(11):3978-3984.
91. Rao T.P., Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ. Res. 2010, 106(12):1798-1806.
92. Pecina-Slaus N. Wnt signal transduction pathway and apoptosis: a review. Cancer Cell Int. 2010, 10:22.
93. Nusse R., Varmus H.E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982, 31(1):99-109.
94. Tsukamoto A.S., et al. Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 1988, 55(4):619-625.
95. Chen G., et al. Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer 2004, 101(6):1345-1356.
96. Moon R.T., et al. WNT and beta-catenin signalling: diseases and therapies. Nat. Rev. Genet. 2004, 5(9):691-701.
97. Qiao L., et al. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res. 2008, 18(4):500-507.
98. Qiao L., et al. Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Lett. 2008, 269(1):67-77.
99. Abdel Aziz M.T., et al. Efficacy of mesenchymal stem cells in suppression of hepatocarcinorigenesis in rats: possible role of Wnt signaling. J. Exp. Clin. Cancer Res. 2011, 30:49.
100. Kandel E.S., Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp. Cell Res. 1999, 253(1):210-229.
101. Vivanco I., Sawyers C.L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2(7):489-501.
102. Parsons D.W., et al. Colorectal cancer: mutations in a signalling pathway. Nature 2005, 436(7052):792.
103. Kirkegaard T., et al. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J. Pathol. 2005, 207(2):139-146.
104. Campbell I.G., et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004, 64(21):7678-7681.
105. Asano T., et al. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells. Oncogene 2004, 23(53):8571-8580.
106. Broderick D.K., et al. Mutations of PIK3CA in anaplastic oligodendrogliomas: high-grade astrocytomas, and medulloblastomas. Cancer Res. 2004, 64(15):5048-5050.
107. Khakoo A.Y., et al. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J. Exp. Med. 2006, 203(5):1235-1247.
108. Davidson B.L., et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc. Natl. Acad. Sci. U. S. A. 2000, 97(7):3428-3432.
109. Fischer A., et al. Gene therapy of severe combined immunodeficiency disease: proof of principle of efficiency and safety issues, gene therapy, primary immunodeficiencies, retrovirus, lentivirus, genome. Bull. Acad. Natl. Med. 2005, 189(5):779-785. discussion 786-8.
110. Nair V. Retrovirus-induced oncogenesis and safety of retroviral vectors. Curr. Opin. Mol. Ther. 2008, 10(5):431-438.
111. Giordano A., Galderisi U., Marino I.R. From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells. J. Cell Physiol. 2007, 211(1):27-35.
112. Morizono K., et al. Multilineage cells from adipose tissue as gene delivery vehicles. Hum. Gene Ther. 2003, 14(1):59-66.
113. Reiser J., et al. Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases. Expert Opin. Biol. Ther. 2005, 5(12):1571-1584.
114. Hall B., et al. Mesenchymal stem cells in cancer: tumor-associated fibroblasts and cell-based delivery vehicles. Int. J. Hematol. 2007, 86(1):8-16.
115. Dong Z., et al. Suppression of angiogenesis: tumorigenicity, and metastasis by human prostate cancer cells engineered to produce interferon-beta. Cancer Res. 1999, 59(4):872-879.
116. Qin X.Q., et al. Interferon-beta induces S phase accumulation selectively in human transformed cells. J. Interferon Cytokine Res. 1997, 17(6):355-367.
117. Streck C.J., et al. Antitumor efficacy of AAV-mediated systemic delivery of interferon-beta. Cancer Gene Ther. 2006, 13(1):99-106.
118. Le Page C., et al. Interferon activation and innate immunity. Rev. Immunogenet. 2000, 2(3):374-386.
119. Ren C., et al. Cancer gene therapy using mesenchymal stem cells expressing interferon-beta in a mouse prostate cancer lung metastasis model. Gene Ther. 2008, 15(21):1446-1453.
120. Hao C., et al. Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells. Cancer Res. 2001, 61(3):1162-1170.
121. Loebinger M.R., et al. TRAIL-expressing mesenchymal stem cells kill the putative cancer stem cell population. Br. J. Cancer 2010, 103(11):1692-1697.
122. Reagan M.R., et al. Stem cell implants for cancer therapy: TRAIL-expressing mesenchymal stem cells target cancer cells in situ. J. Breast Cancer 2012, 15(3):273-282.
123. Wiley S.R., et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995, 3(6):673-682.
124. Schoenhaut D.S., et al. Cloning and expression of murine IL-12. J. Immunol. 1992, 148(11):3433-3440.
125. Chen X.C., et al. Prophylaxis against carcinogenesis in three kinds of unestablished tumor models via IL12-gene-engineered MSCs. Carcinogenesis 2006, 27(12):2434-2441.
126. Elzaouk L., Moelling K., Pavlovic J. Anti-tumor activity of mesenchymal stem cells producing IL-12 in a mouse melanoma model. Exp. Dermatol. 2006, 15(11):865-874.
127. Both G.W. Gene-directed enzyme prodrug therapy for cancer: a glimpse into the future?. Discov. Med. 2009, 8(42):97-103.
128. Rainov N.G., et al. New prodrug activation gene therapy for cancer using cytochrome P450 4B1 and 2-aminoanthracene/4-ipomeanol. Hum. Gene Ther. 1998, 9(9):1261-1273.
129. Both G.W. Recent progress in gene-directed enzyme prodrug therapy: an emerging cancer treatment. Curr. Opin. Mol. Ther. 2009, 11(4):421-432.
130. Kucerova L., et al. Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res. 2007, 67(13):6304-6313.