Tumor heterogeneity: Mechanisms and bases for a reliable application of molecular marker design

International Journal of Molecular Sciences

Volumn 13, Issue 2, 2012, Pages 1951-2011

  Diaz Cano, Salvador J ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Cell segregation; Clonal expansion; Exosome; Metastasis; Neoplasm; Topographic compartments; Tumor heterogeneity; Tumor hypoxia; Tumor microenvironment; Tumor progression

Indexed keywords

MOLECULAR MARKER; PEROXYNITRITE; REACTIVE OXYGEN METABOLITE; GENETIC MARKER; TUMOR MARKER;

CANCER GENETICS; CANCER INVASION; CANCER MORPHOLOGY; CANCER PROGNOSIS; CANCER RISK; CANCER STEM CELL; CANCER SURVIVAL; CARCINOGENESIS; CELL INTERACTION; CHRONIC INFLAMMATION; EARLY CANCER; EPIGENETICS; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENETIC ASSOCIATION; GENETIC HETEROGENEITY; GENETIC VARIABILITY; GENOMIC INSTABILITY; HUMAN; HYPOXIA; MALIGNANT NEOPLASTIC DISEASE; METASTASIS; MOLECULAR CLONING; NONHUMAN; PHENOTYPIC PLASTICITY; PLEIOTROPY; PRECANCER; REVIEW; TUMOR DIFFERENTIATION; TUMOR GROWTH; TUMOR MICROENVIRONMENT; TUMOR VASCULARIZATION; ANIMAL; CLONAL EVOLUTION; DISEASE COURSE; GENETIC MARKER; GENETICS; NEOPLASM; PATHOLOGY; PROCEDURES; STANDARDS;

ANIMALS; CLONAL EVOLUTION; DISEASE PROGRESSION; GENETIC ASSOCIATION STUDIES; GENETIC HETEROGENEITY; GENETIC MARKERS; HUMANS; NEOPLASMS; TUMOR MARKERS, BIOLOGICAL; TUMOR MICROENVIRONMENT;

EID: 84857671060     PISSN: None     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms13021951     Document Type: Review

References (311)

1. Fidler, I.J.; Hart, I.R. Biological diversity in metastatic neoplasms: Origins and implications. Science 1982, 217, 998-1003.
2. Heppner, G.H.; Miller, F.R. The cellular basis of tumor progression. Int. Rev. Cytol. 1998, 177, 1-56.
3. Talmadge, J.E.; Wolman, S.R.; Fidler, I.J. Evidence for the clonal origin of spontaneous metastases. Science 1982, 217, 361-363.
4. Diaz-Cano, S.J. General morphological and biological features of neoplasms: Integration of molecular findings. Histopathology 2008, 53, 1-19.
5. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646-674.
6. Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell 2000, 100, 57-70.
7. Kinzler, K.W.; Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 1996, 87, 159-170.
8. Blanes, A.; Diaz-Cano, S.J. Complementary analysis of microsatellite tumor profile and mismatch repair defects in colorectal carcinomas. World J. Gastroenterol. 2006, 12, 5932-5940.
9. Blanes, A.; Diaz-Cano, S.J. DNA and kinetic heterogeneity during the clonal evolution of adrenocortical proliferative lesions. Hum. Pathol. 2006, 37, 1295-1303.
10. Blanes, A.; Sanchez-Carrillo, J.J.; Diaz-Cano, S.J. Topographic molecular profile of pheochromocytomas: Role of somatic down-regulation of mismatch repair. J. Clin. Endocrinol. Metab. 2006, 91, 1150-1158.
11. Pozo, L.; Sanchez-Carrillo, J.J.; Martinez, A.; Blanes, A.; Diaz-Cano, S.J. Differential kinetic features by tumour topography in cutaneous small-cell neuroendocrine (Merkel cell) carcinomas. J. Eur. Acad. Dermatol. Venereol. 2007, 21, 1220-1228.
12. Kinzler, K.W.; Vogelstein, B. Landscaping the cancer terrain. Science 1998, 280, 1036-1037.
13. Maley, C.C.; Galipeau, P.C.; Finley, J.C.; Wongsurawat, V.J.; Li, X.; Sanchez, C.A.; Paulson, T.G.; Blount, P.L.; Risques, R.A.; Rabinovitch, P.S. et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat. Genet. 2006, 38, 468-473.
14. Iwasa, Y.; Michor, F. Evolutionary dynamics of intratumor heterogeneity. PLoS One 2011, 6, doi:10.1371/journal.pone.0017866.
15. Parmigiani, G.; Boca, S.; Lin, J.; Kinzler, K.W.; Velculescu, V.; Vogelstein, B. Design and analysis issues in genome-wide somatic mutation studies of cancer. Genomics 2009, 93, 17-21.
16. Diaz-Cano, S.J. Clonality studies in the analysis of adrenal medullary proliferations: Application principles and limitations. Endocr. Pathol. 1998, 9, 301-316.
17. Diaz-Cano, S.J. Designing a molecular analysis of clonality in tumours. J. Pathol. 2000, 191, 343-344.
18. Diaz-Cano, S.J.; Blanes, A.; Wolfe, H.J. PCR techniques for clonality assays. Diagn. Mol. Pathol. 2001, 10, 24-33.
19. Pozo-Garcia, L.; Diaz-Cano, S.J. Clonal origin and expansions in neoplasms: Biologic and technical aspects must be considered together. Am. J. Pathol. 2003, 162, 353-354.
20. Leedham, S.J.; Wright, N.A. Human tumour clonality assessment-Flawed but necessary. J. Pathol. 2008, 215, 351-354.
21. Arif, S.; Blanes, A.; Diaz-Cano, S.J. Hashimoto's thyroiditis shares features with early papillary thyroid carcinoma. Histopathology 2002, 41, 357-362.
22. Blanes, A.; Rubio, J.; Martinez, A.; Wolfe, H.J.; Diaz-Cano, S.J. Kinetic profiles by topographic compartments in muscle-invasive transitional cell carcinomas of the bladder: Role of TP53 and NF1 genes. Am. J. Clin. Pathol. 2002, 118, 93-100.
23. Diaz-Cano, S.J.; Blanes, A.; Rubio, J.; Matilla, A.; Wolfe, H.J. Molecular evolution and intratumor heterogeneity by topographic compartments in muscle-invasive transitional cell carcinoma of the urinary bladder. Lab. Invest. 2000, 80, 279-289.
24. Diaz-Cano, S.J.; de Miguel, M.; Blanes, A.; Tashjian, R.; Galera, H.; Wolfe, H.J. Clonality as expression of distinctive cell kinetics patterns in nodular hyperplasias and adenomas of the adrenal cortex. Am. J. Pathol. 2000, 156, 311-319.
25. Diaz-Cano, S.J.; de Miguel, M.; Blanes, A.; Tashjian, R.; Galera, H.; Wolfe, H.J. Clonal patterns in phaeochromocytomas and MEN-2A adrenal medullary hyperplasias: Histological and kinetic correlates. J. Pathol. 2000, 192, 221-228.
26. Jones, P.A. DNA methylation and cancer. Cancer Res. 1986, 46, 461-466.
27. Jones, P.A.; Baylin, S.B. The epigenomics of cancer. Cell 2007, 128, 683-692.
28. Diaz-Cano, S.J. Are PCR artifacts in microdissected samples preventable? Hum. Pathol. 2001, 32, 1415-1416.
29. Diaz-Cano, S.J.; de Miguel, M.; Blanes, A.; Galera, H.; Wolfe, H.J. Contribution of the microvessel network to the clonal and kinetic profiles of adrenal cortical proliferative lesions. Hum. Pathol. 2001, 32, 1232-1239.
30. Blanes, A.; Rubio, J.; Sanchez-Carrillo, J.J.; Diaz-Cano, S.J. Coexistent intraurothelial carcinoma and muscle-invasive urothelial carcinoma of the bladder: Clonality and somatic down-regulation of DNA mismatch repair. Hum. Pathol. 2009, 40, 988-997.
31. Diaz-Cano, S.J.; de Miguel, M.; Blanes, A.; Tashjian, R.; Wolfe, H.J. Germline RET 634 mutation positive MEN 2A-related C-cell hyperplasias have genetic features consistent with intraepithelial neoplasia. J. Clin. Endocrinol. Metab. 2001, 86, 3948-3957.
32. Rubio, J.; Blanes, A.; Sanchez-Carrillo, J.J.; Diaz-Cano, S.J. Microsatellite abnormalities and somatic down-regulation of mismatch repair characterize nodular-trabecular muscle-invasive urothelial carcinoma of the bladder. Histopathology 2007, 51, 458-467.
33. Polyak, K.; Haviv, I.; Campbell, I.G. Co-evolution of tumor cells and their microenvironment. Trends Genet. 2009, 25, 30-38.
34. Husain, E.A.; Mein, C.; Pozo, L.; Blanes, A.; Diaz-Cano, S.J. Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi. Mod. Pathol. 2011, 24, 471-486.
35. Visvader, J.E.; Lindeman, G.J. Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nat. Rev. Cancer 2008, 8, 755-768.
36. Rossi, D.J.; Jamieson, C.H.; Weissman, I.L. Stems cells and the pathways to aging and cancer. Cell 2008, 132, 681-696.
37. Tan, B.T.; Park, C.Y.; Ailles, L.E.; Weissman, I.L. The cancer stem cell hypothesis: A work in progress. Lab. Invest. 2006, 86, 1203-1207.
38. Ailles, L.E.; Weissman, I.L. Cancer stem cells in solid tumors. Curr. Opin. Biotechnol. 2007, 18, 460-466.
39. Cho, R.W.; Clarke, M.F. Recent advances in cancer stem cells. Curr. Opin. Genet. Dev. 2008, 18, 48-53.
40. Kelly, P.N.; Dakic, A.; Adams, J.M.; Nutt, S.L.; Strasser, A. Tumor growth need not be driven by rare cancer stem cells. Science 2007, 317, 337.
41. Kern, S.E.; Shibata, D. The fuzzy math of solid tumor stem cells: A perspective. Cancer Res 2007, 67, 8985-8988.
42. Park, S.Y.; Gonen, M.; Kim, H.J.; Michor, F.; Polyak, K. Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. J. Clin. Invest. 2010, 120, 636-644.
43. Marotta, L.L.; Almendro, V.; Marusyk, A.; Shipitsin, M.; Schemme, J.; Walker, S.R.; Bloushtain-Qimron, N.; Kim, J.J.; Choudhury, S.A.; Maruyama, R. et al. The JAK2/STAT3 signaling pathway is required for growth of CD44CD24 stem cell-like breast cancer cells in human tumors. J. Clin. Invest. 2011, 121, 2723-2735.
44. Hill, R.P. Identifying cancer stem cells in solid tumors: Case not proven. Cancer Res. 2006, 66, 1891-1895.
45. Burkert, J.; Wright, N.A.; Alison, M.R. Stem cells and cancer: An intimate relationship. J. Pathol. 2006, 209, 287-297.
46. Garcia, S.B.; Park, H.S.; Novelli, M.; Wright, N.A. Field cancerization, clonality, and epithelial stem cells: The spread of mutated clones in epithelial sheets. J. Pathol. 1999, 187, 61-81.
47. Poulsom, R.; Alison, M.R.; Forbes, S.J.; Wright, N.A. Adult stem cell plasticity. J. Pathol. 2002, 197, 441-456.
48. Durrett, R.; Foo, J.; Leder, K.; Mayberry, J.; Michor, F. Intratumor heterogeneity in evolutionary models of tumor progression. Genetics 2011, 188, 461-477.
49. Spencer, S.L.; Gaudet, S.; Albeck, J.G.; Burke, J.M.; Sorger, P.K. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 2009, 459, 428-432.
50. Sanz-Moreno, V.; Gadea, G.; Ahn, J.; Paterson, H.; Marra, P.; Pinner, S.; Sahai, E.; Marshall, C.J. Rac activation and inactivation control plasticity of tumor cell movement. Cell 2008, 135, 510-523.
51. Nowell, P.C. The clonal evolution of tumor cell populations. Science 1976, 194, 23-28.
52. Shah, N.P.; Nicoll, J.M.; Nagar, B.; Gorre, M.E.; Paquette, R.L.; Kuriyan, J.; Sawyers, C.L. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002, 2, 117-125.
53. Corless, C.L.; Heinrich, M.C. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu. Rev. Pathol. 2008, 3, 557-586.
54. Edwards, S.L.; Brough, R.; Lord, C.J.; Natrajan, R.; Vatcheva, R.; Levine, D.A.; Boyd, J.; Reis-Filho, J.S.; Ashworth, A. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 2008, 451, 1111-1115.
55. Blagosklonny, M.V. Oncogenic resistance to growth-limiting conditions. Nat. Rev. Cancer 2002, 2, 221-225.
56. Laconi, E.; Doratiotto, S.; Vineis, P. The microenvironments of multistage carcinogenesis. Semin. Cancer Biol. 2008, 18, 322-329.
57. Laconi, E.; Sonnenschein, C. Cancer development at tissue level. Semin. Cancer Biol. 2008, 18, 303-304.
58. Bissell, M.J.; Labarge, M.A. Context, tissue plasticity, and cancer: Are tumor stem cells also regulated by the microenvironment? Cancer Cell 2005, 7, 17-23.
59. Polyak, K. Heterogeneity in breast cancer. J. Clin. Invest. 2011, 121, 3786-3788.
60. Merlo, L.M.; Pepper, J.W.; Reid, B.J.; Maley, C.C. Cancer as an evolutionary and ecological process. Nat. Rev. Cancer 2006, 6, 924-935.
61. Marusyk, A.; DeGregori, J. Declining cellular fitness with age promotes cancer initiation by selecting for adaptive oncogenic mutations. Biochim. Biophys. Acta 2008, 1785, 1-11.
62. Lowe, S.W.; Cepero, E.; Evan, G. Intrinsic tumour suppression. Nature 2004, 432, 307-315.
63. Zhang, J.; Grindley, J.C.; Yin, T.; Jayasinghe, S.; He, X.C.; Ross, J.T.; Haug, J.S.; Rupp, D.; Porter-Westpfahl, K.S.; Wiedemann, L.M. et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006, 441, 518-522.
64. Michor, F.; Iwasa, Y.; Nowak, M.A. Dynamics of cancer progression. Nat. Rev. Cancer 2004, 4, 197-205.
65. Michor, F.; Polyak, K. The origins and implications of intratumor heterogeneity. Cancer Prev. Res. (Phila.) 2010, 3, 1361-1364.
66. Marusyk, A.; Casas-Selves, M.; Henry, C.J.; Zaberezhnyy, V.; Klawitter, J.; Christians, U.; DeGregori, J. Irradiation alters selection for oncogenic mutations in hematopoietic progenitors. Cancer Res. 2009, 69, 7262-7269.
67. Laconi, S.; Pani, P.; Pillai, S.; Pasciu, D.; Sarma, D.S.; Laconi, E. A growth-constrained environment drives tumor progression invivo. Proc. Natl. Acad. Sci. USA 2001, 98, 7806-7811.
68. Nagy, J.D. Competition and natural selection in a mathematical model of cancer. Bull. Math. Biol. 2004, 66, 663-687.
69. Devireddy, L.R.; Gazin, C.; Zhu, X.; Green, M.R. A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 2005, 123, 1293-1305.
70. Guba, M.; Cernaianu, G.; Koehl, G.; Geissler, E.K.; Jauch, K.W.; Anthuber, M.; Falk, W.; Steinbauer, M. A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Res. 2001, 61, 5575-5579.
71. Axelrod, R.; Axelrod, D.E.; Pienta, K.J. Evolution of cooperation among tumor cells. Proc. Natl. Acad. Sci. USA 2006, 103, 13474-13479.
72. Mallepell, S.; Krust, A.; Chambon, P.; Brisken, C. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proc. Natl. Acad. Sci. USA 2006, 103, 2196-2201.
73. Godar, S.; Ince, T.A.; Bell, G.W.; Feldser, D.; Donaher, J.L.; Bergh, J.; Liu, A.; Miu, K.; Watnick, R.S.; Reinhardt, F. et al. Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell 2008, 134, 62-73.
74. McAllister, S.S.; Gifford, A.M.; Greiner, A.L.; Kelleher, S.P.; Saelzler, M.P.; Ince, T.A.; Reinhardt, F.; Harris, L.N.; Hylander, B.L.; Repasky, E.A. et al. Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 2008, 133, 994-1005.
75. Yamamoto, K.; Hanada, R.; Kikuchi, A.; Ichikawa, M.; Aihara, T.; Oguma, E.; Moritani, T.; Shimanuki, Y.; Tanimura, M.; Hayashi, Y. Spontaneous regression of localized neuroblastoma detected by mass screening. J. Clin. Oncol. 1998, 16, 1265-1269.
76. Axelrod, R.; Hamilton, W.D. The evolution of cooperation. Science 1981, 211, 1390-1396.
77. Lyons, J.G.; Lobo, E.; Martorana, A.M.; Myerscough, M.R. Clonal diversity in carcinomas: Its implications for tumour progression and the contribution made to it by epithelial-mesenchymal transitions. Clin. Exp. Metastasis 2008, 25, 665-677.
78. Morrison, S.J.; Spradling, A.C. Stem cells and niches: Mechanisms that promote stem cell maintenance throughout life. Cell 2008, 132, 598-611.
79. Reddig, P.J.; Juliano, R.L. Clinging to life: Cell to matrix adhesion and cell survival. Cancer Metastasis Rev. 2005, 24, 425-439.
80. Tlsty, T.D.; Coussens, L.M. Tumor stroma and regulation of cancer development. Annu. Rev. Pathol. 2006, 1, 119-150.
81. Baithun, S.I.; Naase, M.; Blanes, A.; Diaz-Cano, S.J. Molecular and kinetic features of transitional cell carcinomas of the bladder: Biological and clinical implications. Virchows Arch. 2001, 438, 289-297.
82. Laconi, E. The evolving concept of tumor microenvironments. Bioessays 2007, 29, 738-744.
83. Huang, L.E.; Bindra, R.S.; Glazer, P.M.; Harris, A.L. Hypoxia-induced genetic instability- Calculated mechanism underlying tumor progression. J. Mol. Med. (Berl.) 2007, 85, 139-148.
84. Hahn, W.C.; Counter, C.M.; Lundberg, A.S.; Beijersbergen, R.L.; Brooks, M.W.; Weinberg, R.A. Creation of human tumour cells with defined genetic elements. Nature 1999, 400, 464-468.
85. Rubin, H. Microenvironmental regulation of the initiated cell. Adv. Cancer Res. 2003, 90, 1-62.
86. Mudgil, A.V.; Segal, N.; Andriani, F.; Wang, Y.; Fusenig, N.E.; Garlick, J.A. Ultraviolet B irradiation induces expansion of intraepithelial tumor cells in a tissue model of early cancer progression. J. Invest. Dermatol. 2003, 121, 191-197.
87. Schollnberger, H.; Manuguerra, M.; Bijwaard, H.; Boshuizen, H.; Altenburg, H.P.; Rispens, S.M.; Brugmans, M.J.; Vineis, P. Analysis of epidemiological cohort data on smoking effects and lung cancer with a multi-stage cancer model. Carcinogenesis 2006, 27, 1432-1444.
88. Farber, E.; Rubin, H. Cellular adaptation in the origin and development of cancer. Cancer Res. 1991, 51, 2751-2761.
89. Cristini, V.; Frieboes, H.B.; Gatenby, R.; Caserta, S.; Ferrari, M.; Sinek, J. Morphologic instability and cancer invasion. Clin. Cancer Res. 2005, 11, 6772-6779.
90. Cayama, E.; Tsuda, H.; Sarma, D.S.; Farber, E. Initiation of chemical carcinogenesis requires cell proliferation. Nature 1978, 275, 60-62.
91. Breivik, J. The evolutionary origin of genetic instability in cancer development. Semin. Cancer Biol 2005, 15, 51-60.
92. West, R.B.; Rubin, B.P.; Miller, M.A.; Subramanian, S.; Kaygusuz, G.; Montgomery, K.; Zhu, S.; Marinelli, R.J.; De Luca, A.; Downs-Kelly, E. et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc. Natl. Acad. Sci. USA 2006, 103, 690-695.
93. van Vugt, M.A.; Bras, A.; Medema, R.H. Restarting the cell cycle when the checkpoint comes to a halt. Cancer Res. 2005, 65, 7037-7040.
94. Jonason, A.S.; Kunala, S.; Price, G.J.; Restifo, R.J.; Spinelli, H.M.; Persing, J.A.; Leffell, D.J.; Tarone, R.E.; Brash, D.E. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc. Natl. Acad. Sci. USA 1996, 93, 14025-14029.
95. Laconi, E.; Pani, P.; Farber, E. The resistance phenotype in the development and treatment of cancer. Lancet Oncol. 2000, 1, 235-241.
96. Marongiu, F.; Doratiotto, S.; Montisci, S.; Pani, P.; Laconi, E. Liver repopulation and carcinogenesis: Two sides of the same coin? Am. J. Pathol. 2008, 172, 857-864.
97. Campisi, J. Aging and cancer cell biology, 2007. Aging Cell 2007, 6, 261-263.
98. Sharpless, N.E.; DePinho, R.A. How stem cells age and why this makes us grow old. Nat. Rev. Mol. Cell Biol. 2007, 8, 703-713.
99. McCullough, K.D.; Coleman, W.B.; Smith, G.J.; Grishan, J.W. Age-dependent regulation of the tumorigenic potential of neoplastically transformed rat liver epithelial cells by the liver microenvironment. Cancer Res. 1994, 54, 3668-3671.
100. Pasciu, D.; Montisci, S.; Greco, M.; Doratiotto, S.; Pitzalis, S.; Pani, P.; Laconi, S, Laconi, E. Aging is associated with increased clonogenic potential in rat liver in vivo. Aging Cell 2006, 5, 373-377.
101. Krtolica, A.; Parrinello, S.; Lockett, S.; Desprez, P.Y.; Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging. Proc. Natl. Acad. Sci. USA 2001, 98, 12072-12077.
102. Liu, D.; Hornsby, P.J. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 2007, 67, 3117-3126.
103. Trost, T.M.; Lausch, E.U.; Fees, S.A.; Schmitt, S.; Enklaar, T.; Reutzel, D.; Brixel, L.R.; Schmidtke, P.; Maringer, M.; Schiffer, I.B. et al. Premature senescence is a primary fail-safe mechanism of ERBB2-driven tumorigenesis in breast carcinoma cells. Cancer Res. 2005, 65, 840-849.
104. Philip, M.; Rowley, D.A.; Schreiber, H. Inflammation as a tumor promoter in cancer induction. Semin. Cancer Biol. 2004, 14, 433-439.
105. Hussain, S.P.; Harris, C.C. Inflammation and cancer: An ancient link with novel potentials. Int. J. Cancer 2007, 121, 2373-2380.
106. Prehn, R.T. R egeneration versus neoplastic growth. Carcinogenesis 1997, 18, 1439-1444.
107. Correa, P.; Houghton, J. Carcinogenesis of Helicobacter pylori. Gastroenterology 2007, 133, 659-672.
108. De Marzo, A.M.; Marchi, V.L.; Epstein, J.I.; Nelson, W.G. Proliferative inflammatory atrophy of the prostate: Implications for prostatic carcinogenesis. Am. J. Pathol. 1999, 155, 1985-1992.
109. De Marzo, A.M.; Nakai, Y.; Nelson, W.G. Inflammation, atrophy, and prostate carcinogenesis. Urol. Oncol. 2007, 25, 398-400.
110. Fox, J.G.; Wang, T.C. Inflammation, atrophy, and gastric cancer. J. Clin. Invest. 2007, 117, 60-69.
111. Harpaz, N. Neoplastic precursor lesions related to the development of cancer in inflammatory bowel disease. Gastroenterol. Clin. North Am. 2007, 36, 901-926, vii-viii.
112. Rass, U.; Ahel, I.; West, S.C. Defective DNA repair and neurodegenerative disease. Cell 2007, 130, 991-1004.
113. de Boer, J.; Andressoo, J.O.; de Wit, J.; Huijmans, J.; Beems, R.B.; van Steeg, H.; Weeda, G.; van der Horst, G.T.; van Leeuwen, W.; Themmen, A.P. et al. Premature aging in mice deficient in DNA repair and transcription. Science 2002, 296, 1276-1279.
114. Bielas, J.H.; Loeb, L.A. Mutator phenotype in cancer: Timing and perspectives. Environ. Mol. Mutagen. 2005, 45, 206-213.
115. Bardelli, A.; Cahill, D.P.; Lederer, G.; Speicher, M.R.; Kinzler, K.W.; Vogelstein, B.; Lengauer, C. Carcinogen-specific induction of genetic instability. Proc. Natl. Acad. Sci. USA 2001, 98, 5770-5775.
116. Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860-867.
117. Ellis, L.M.; Hicklin, D.J. VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nat. Rev. Cancer 2008, 8, 579-591.
118. Yang, L.; Huang, J.; Ren, X.; Gorska, A.E.; Chytil, A.; Aakre, M.; Carbone, D.P.; Matrisian, L.M.; Richmond, A.; Lin, P.C. et al. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 2008, 13, 23-35.
119. Gabrilovich, D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev. Immunol. 2004, 4, 941-952.
120. Marx, J. Cancer biology. All in the stroma: Cancer's Cosa Nostra. Science 2008, 320, 38-41.
121. Marx, J. Cancer immunology. Cancer's bulwark against immune attack: MDS cells. Science 2008, 319, 154-156.
122. Nonaka, K.; Saio, M.; Suwa, T.; Frey, A.B.; Umemura, N.; Imai, H.; Ouyang, G.F.; Osada, S.; Balazs, M.; Adany, R. et al. Skewing the Th cell phenotype toward Th1 alters the maturation of tumor-infiltrating mononuclear phagocytes. J. Leukoc. Biol. 2008, 84, 679-688.
123. Umemura, N.; Saio, M.; Suwa, T.; Kitoh, Y.; Bai, J.; Nonaka, K.; Ouyang, G.-F.; Okada, M.; Balazs, M.; Adany, R. et al. Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J. Leukoc. Biol. 2008, 83, 1136-1144.
124. Mantovani, A.; Sica, A.; Allavena, P.; Garlanda, C.; Locati, M. Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum. Immunol. 2009, 70, 325-330.
125. Sica, A.; Larghi, P.; Mancino, A.; Rubino, L.; Porta, C.; Totaro, M.G.; Rimoldi, M.; Biswas, S.K.; Allavena, P.; Mantovani, A. Macrophage polarization in tumour progression. Semin. Cancer Biol. 2008, 18, 349-355.
126. Mantovani, A.; Sica, A. Macrophages, innate immunity and cancer: Balance, tolerance, and diversity. Curr. Opin. Immunol. 2010, 22, 231-237.
127. Sinha, P.; Clements, V.K.; Miller, S.; Ostrand-Rosenberg, S. Tumor immunity: A balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol. Immunother. 2005, 54, 1137-1142.
128. Sinha, P.; Clements, V.K.; Ostrand-Rosenberg, S. Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J. Immunol. 2005, 174, 636-645.
129. Sinha, P.; Clements, V.K.; Ostrand-Rosenberg, S. Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res. 2005, 65, 11743-11751.
130. Lewis, C.E.; Pollard, J.W. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006, 66, 605-612.
131. Yang, L.; DeBusk, L.M.; Fukuda, K.; Fingleton, B.; Green-Jarvis, B.; Shyr, Y.; Matrisian, L.M.; Carbone, D.P.; Lin, P.C. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004, 6, 409-421.
132. Sinha, P.; Clements, V.K.; Bunt, S.K.; Albelda, S.M.; Ostrand-Rosenberg, S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J. Immunol. 2007, 179, 977-983.
133. Condeelis, J.; Pollard, J.W. Macrophages: Obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006, 124, 263-266.
134. Larsen, M.; Tazzyman, S.; Lund, E.L.; Junker, N.; Lewis, C.E.; Kristjansen, P.E.; Murdoch, C. Hypoxia-induced secretion of macrophage migration-inhibitory factor from MCF-7 breast cancer cells is regulated in a hypoxia-inducible factor-independent manner. Cancer Lett. 2008, 265, 239-249.
135. Bosco, M.C.; Puppo, M.; Blengio, F.; Fraone, T.; Cappello, P.; Giovarelli, M.; Varesio, L. Monocytes and dendritic cells in a hypoxic environment: Spotlights on chemotaxis and migration. Immunobiology 2008, 213, 733-749.
136. Youn, J.I.; Nagaraj, S.; Collazo, M.; Gabrilovich, D.I. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J. Immunol. 2008, 181, 5791-5802.
137. Movahedi, K.; Guilliams, M.; van den Bossche, J.; van den Bergh, R.; Gysemans, C.; Beschin, A.; De Baetselier, P.; Van Ginderachter, J.A. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 2008, 111, 4233-4244.
138. Kusmartsev, S.; Gabrilovich, D.I. Inhibition of myeloid cell differentiation in cancer: The role of reactive oxygen species. J. Leukoc. Biol. 2003, 74, 186-196.
139. Sinha, P.; Clements, V.K.; Fulton, A.M.; Ostrand-Rosenberg, S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007, 67, 4507-4513.
140. Bronte, V.; Serafini, P.; Mazzoni, A.; Segal, D.M.; Zanovello, P. L-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol. 2003, 24, 302-306.
141. Almand, B.; Clark, J.I.; Nikitina, E.; van Beynen, J.; English, N.R.; Knight, S.C.; Carbone, D.P.; Gabrilovich, D.I. Increased production of immature myeloid cells in cancer patients: A mechanism of immunosuppression in cancer. J. Immunol. 2001, 166, 678-689.
142. Baniyash, M. TCR zeta-chain downregulation: Curtailing an excessive inflammatory immune response. Nat. Rev. Immunol. 2004, 4, 675-687.
143. Bunt, S.K.; Sinha, P.; Clements, V.K.; Leips, J.; Ostrand-Rosenberg, S. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J. Immunol. 2006, 176, 284-290.
144. Bunt, S.K.; Yang, L.; Sinha, P.; Clements, V.K.; Leips, J.; Ostrand-Rosenberg, S. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 2007, 67, 10019-10026.
145. Simpson, A.J. The natural somatic mutation frequency and human carcinogenesis. Adv. Cancer Res. 1997, 71, 209-240.
146. Farber, E.; Cameron, R. The sequential analysis of cancer development. Adv. Cancer Res. 1980, 31, 125-226.
147. Bindra, R.S.; Glazer, P.M. Genetic instability and the tumor microenvironment: Towards the concept of microenvironment-induced mutagenesis. Mutat. Res. 2005, 569, 75-85.
148. Sneddon, J.B.; Werb, Z. Location, location, location: The cancer stem cell niche. Cell Stem Cell 2007, 1, 607-611.
149. Calabrese, C.; Poppleton, H.; Kocak, M.; Hogg, T.L.; Fuller, C.; Hamner, B.; Oh, E.Y.; Gaber, M.W.; Finklestein, D.; Allen, M. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007, 11, 69-82.
150. Veeravagu, A.; Bababeygy, S.R.; Kalani, M.Y.; Hou, L.C.; Tse, V. The cancer stem cell-vascular niche complex in brain tumor formation. Stem Cells Dev 2008, 17, 859-867.
151. Gilbertson, R.J.; Gutmann, D.H. Tumorigenesis in the brain: Location, location, location. Cancer Res. 2007, 67, 5579-5582.
152. Gilbertson, R.J.; Rich, J.N. Making a tumour's bed: Glioblastoma stem cells and the vascular niche. Nat. Rev. Cancer 2007, 7, 733-736.
153. Croker, A.K.; Goodale, D.; Chu, J.; Postenka, C.; Hedley, B.D.; Hess, D.A.; Allan, A.L. High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J. Cell. Mol. Med. 2009, 13, 2236-2252.
154. Croker, A.K.; Allan, A.L. Cancer stem cells: Implications for the progression and treatment of metastatic disease. J. Cell. Mol. Med. 2008, 12, 374-390.
155. Campbell, I.; Qiu, W.; Haviv, I. Genetic changes in tumour microenvironments. J. Pathol. 2011, 223, 450-458.
156. Korkaya, H.; Liu, S.; Wicha, M.S. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J. Clin. Invest 2011, 121, 3804-3809.
157. Weinberg, R.A. Coevolution in the tumor microenvironment. Nat. Genet. 2008, 40, 494-495.
158. Whiteside, T.L. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008, 27, 5904-5912.
159. Ben-Baruch, A. Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: Reciprocal tumor-microenvironment interactions. Breast Cancer Res. 2003, 5, 31-36.
160. Zipin-Roitman, A.; Meshel, T.; Sagi-Assif, O.; Shalmon, B.; Avivi, C.; Pfeffer, R.M.; Witz, I.P.; Ben-Baruch, A. CXCL10 promotes invasion-related properties in human colorectal carcinoma cells. Cancer Res. 2007, 67, 3396-3405.
161. Malumbres, M.; Barbacid, M. To cycle or not to cycle: A critical decision in cancer. Nat. Rev. Cancer 2001, 1, 222-231.
162. Hersey, P.; Zhang, X.D. How melanoma cells evade trail-induced apoptosis. Nat. Rev. Cancer 2001, 1, 142-150.
163. Anderson, A.R.; Hassanein, M.; Branch, K.M.; Lu, J.; Lobdell, N.A.; Maier, J.; Basanta, D.; Weidow, B.; Narasanna, A.; Arteaga, C.L. et al. Microenvironmental independence associated with tumor progression. Cancer Res. 2009, 69, 8797-8806.
164. Anderson, A.R.; Rejniak, K.A.; Gerlee, P.; Quaranta, V. Microenvironment driven invasion: A multiscale multimodel investigation. J. Math. Biol. 2009, 58, 579-624.
165. Anderson, A.R.; Weaver, A.M.; Cummings, P.T.; Quaranta, V. Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell 2006, 127, 905-915.
166. Jimenez, J.J.; Blanes, A.; Diaz-Cano, S.J. Microsatellite instability in colon cancer. N. Engl. J. Med. 2003, 349, 1774-1776.
167. Diaz-Cano, S.J. Molecular mechanisms in melanoma. N. Engl. J. Med. 2006, 355, 1395-1396.
168. Pozo, L.; Husein, E.; Blanes, A.; Diaz-Cano, S.J. The correlation of regression with the grade of dysplasia (atypia) in melanocytic naevi. Histopathology 2008, 52, 387-389.
169. Husemann, Y.; Geigl, J.B.; Schubert, F.; Musiani, P.; Meyer, M.; Burghart, E.; Forni, G.; Eils, R.; Fehm, T.; Riethmüller, G. et al. Systemic spread is an early step in breast cancer. Cancer Cell 2008, 13, 58-68.
170. Arif, S.; Patel, J.; Blanes, A.; Diaz-Cano, S.J. Cytoarchitectural and kinetic features in the histological evaluation of follicular thyroid neoplasms. Histopathology 2007, 50, 750-763.
171. Boone, C.W.; Kelloff, G.J.; Freedman, L.S. Intraepithelial and postinvasive neoplasia as a stochastic continuum of clonal evolution, and its relationship to mechanisms of chemopreventive drug action. J. Cell. Biochem. Suppl. 1993, 17G, 14-25.
172. Namba, R.; Maglione, J.E.; Davis, R.R.; Baron, C.A.; Liu, S.; Carmack, C.E.; Young, L.J.T.; Borowsky, A.D.; Cardiff, R.D.; Gregg, J.P. Heterogeneity of mammary lesions represent molecular differences. BMC Cancer 2006, 6, doi:10.1186/1471-2407-6-275.
173. Steeg, P.S. Tumor metastasis: Mechanistic insights and clinical challenges. Nat. Med. 2006, 12, 895-904.
174. Steeg, P.S. Cancer: Micromanagement of metastasis. Nature 2007, 449, 671-673.
175. Talmadge, J.E. Clonal selection of metastasis within the life history of a tumor. Cancer Res. 2007, 67, 11471-11475.
176. Christofori, G. New signals from the invasive front. Nature 2006, 441, 444-450.
177. Gupta, G.P.; Massague, J. Cancer metastasis: Building a framework. Cell 2006, 127, 679-695.
178. Nguyen, D.X. Tracing the origins of metastasis. J Pathol 2011, 223, 195-204.
179. Nguyen, D.X.; Massague, J. Genetic determinants of cancer metastasis. Nat. Rev. Genet. 2007, 8, 341-352.
180. Li, F.; Tiede, B.; Massague, J.; Kang, Y. Beyond tumorigenesis: Cancer stem cells in metastasis. Cell Res. 2007, 17, 3-14.
181. Wicha, M.S. Cancer stem cells and metastasis: Lethal seeds. Clin. Cancer Res. 2006, 12, 5606-5607.
182. Kaplan, R.N.; Psaila, B.; Lyden, D. Bone marrow cells in the 'pre-metastatic niche': Within bone and beyond. Cancer Metastasis Rev. 2006, 25, 521-529.
183. Kaplan, R.N.; Rafii, S.; Lyden, D. Preparing the "soil": The premetastatic niche. Cancer Res. 2006, 66, 11089-11093.
184. Kaplan, R.N.; Riba, R.D.; Zacharoulis, S.; Bramley, A.H.; Vincent, L.; Costa, C.; MacDonald, D.D.; Jin, D.K.; Shido, K.; Kerns, S.A. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005, 438, 820-827.
185. Bissig, H.; Richter, J.; Desper, R.; Meier, V.; Schraml, P.; Schäffer, A.A.; Sauter, G.; Mihatsch, M.J.; Moch, H. Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridization. Am. J. Pathol. 1999, 155, 267-274.
186. Cheng, L.; Bostwick, D.G.; Li, G.; Wang, Q.; Hu, N.; Vortmeyer, A.O.; Zhuang, Z. Allelic imbalance in the clonal evolution of prostate carcinoma. Cancer 1999, 85, 2017-2022.
187. Kuukasjarvi, T.; Karhu, R.; Tanner, M.; Kähkönen, M.; Schäffer, A.; Nupponen, N.; Pennanen, S.; Kallioniemi, A.; Kallioniemi, O.P.; Isola, J. Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res. 1997, 57, 1597-1604.
188. Ramaswamy, S.; Ross, K.N.; Lander, E.S.; Golub, T.R. A molecular signature of metastasis in primary solid tumors. Nat. Genet. 2003, 33, 49-54.
189. Weigelt, B.; Glas, A.M.; Wessels, L.F.; Witteveen, A.T.; Peterse, J.L.; van't Veer, L.J. Gene expression profiles of primary breast tumors maintained in distant metastases. Proc. Natl. Acad. Sci. USA 2003, 100, 15901-15905.
190. Weigelt, B.; Hu, Z.; He, X.; Livasy, C.; Carey, L.A.; Ewend, M.G.; Glas, A.M.; Perou, C.M.; van't Veer, L.J. Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res. 2005, 65, 9155-9158.
191. Liu, W.; Laitinen, S.; Khan, S.; Vihinen, M.; Kowalski, J.; Yu, G.; Chen, L.; Ewing, C.M.; Eisenberger, M.A. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat. Med. 2009, 15, 559-565.
192. Ruijter, E.T.; van de Kaa, C.A.; Schalken, J.A.; Debruyne, F.M.; Ruiter, D.J. Histological grade heterogeneity in multifocal prostate cancer. Biological and clinical implications. J. Pathol. 1996, 180, 295-299.
193. Alvarado, C.; Beitel, L.K.; Sircar, K.; Aprikian, A.; Trifiro, M.; Gottlieb, B. Somatic mosaicism and cancer: A micro-genetic examination into the role of the androgen receptor gene in prostate cancer. Cancer Res. 2005, 65, 8514-8518.
194. Shah, S.P.; Morin, R.D.; Khattra, J.; Prentice, L.; Pugh, T.; Burleigh, A.; Delaney, A.; Gelmon, K.; Guliany, R.; Senz, J. et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 2009, 461, 809-813.
195. Holmgren, L.; O'Reilly, M.S.; Folkman, J. Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat. Med. 1995, 1, 149-153.
196. Braun, S.; Pantel, K.; Muller, P.; Janni, W.; Hepp, F.; Kentenich, C.R.; Gastroph, S.; Wischnik, A.; Dimpfl, T.; Kindermann, G. et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N. Engl. J. Med. 2000, 342, 525-533.
197. Diaz-Cano, S.J. Bone marrow metastases in breast cancer. N. Engl. J. Med. 2000, 343, 577.
198. Passlick, B.; Izbicki, J.R.; Kubuschok, B.; Nathrath, W.; Thetter, O.; Pichlmeier, U.; Schweiberer, L.; Riethmüller, G.; Pantel, K. Immunohistochemical assessment of individual tumor cells in lymph nodes of patients with non-small-cell lung cancer. J. Clin. Oncol. 1994, 12, 1827-1832.
199. Schlimok, G.; Funke, I.; Holzmann, B.; Göttlinger, G.; Schmidt, G.; Häuser, H.; Swierkot, S.; Warnecke, H.H.; Schneider, B.; Koprowski, H. Micrometastatic cancer cells in bone marrow: In vitro detection with anti-cytokeratin and in vivo labeling with anti-17-1A monoclonal antibodies. Proc. Natl. Acad. Sci. USA 1987, 84, 8672-8676.
200. Smith, B.L. Approaches to breast-cancer staging. N. Engl. J. Med. 2000, 342, 580-581.
201. Klein, C.A.; Schmidt-Kittler, O.; Schardt, J.A.; Pantel, K.; Speicher, M.R.; Riethmuller, G. Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells. Proc. Natl. Acad. Sci. USA 1999, 96, 4494-4499.
202. Klein, C.A.; Blankenstein, T.J.; Schmidt-Kittler, O.; Petronio, M.; Polzer, B.; Stoecklein, N.H.; Riethmüller, G. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 2002, 360, 683-689.
203. Schmidt-Kittler, O.; Ragg, T.; Daskalakis, A.; Granzow, M.; Ahr, A.; Blankenstein, T.J.F.; Kaufmann, M.; Diebold, J.; Arnholdt, H.; Müller P. et al. From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression. Proc. Natl. Acad. Sci. USA 2003, 100, 7737-7742.
204. Bedenne, L.; Michel, P.; Bouche, O.; Milan, C.; Mariette, C.; Conroy, T.; Pezet, D.; Roullet, B.; Seitz, J.-F.; Herr, J.-P. et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J. Clin. Oncol. 2007, 25, 1160-1168.
205. Stoecklein, N.H.; Hosch, S.B.; Bezler, M.; Stern, F.; Hartmann, C.H.; Vay, C.; Siegmund, A.; Scheunemann, P.; Schurr, P.; Knoefel, W.T. et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell 2008, 13, 441-453.
206. Podsypanina, K.; Du, Y.C.; Jechlinger, M.; Beverly, L.J.; Hambardzumyan, D.; Varmus, H. Seeding and propagation of untransformed mouse mammary cells in the lung. Science 2008, 321, 1841-1844.
207. Gadi, V.K.; Nelson, J.L. Fetal microchimerism in women with breast cancer. Cancer Res. 2007, 67, 9035-9038.
208. Solakoglu, O.; Maierhofer, C.; Lahr, G.; Breit, E.; Scheunemann, P.; Heumos, I.; Pichlmeier, U.; Schlimok, G.; Oberneder, R.; Köllermann, M.W. et al. Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proc. Natl. Acad. Sci. USA 2002, 99, 2246-2251.
209. Gangnus, R.; Langer, S.; Breit, E.; Pantel, K.; Speicher, M.R. Genomic profiling of viable and proliferative micrometastatic cells from early-stage breast cancer patients. Clin Cancer Res. 2004, 10, 3457-3464.
210. Abbruzzese, J.L.; Abbruzzese, M.C.; Hess, K.R.; Raber, M.N.; Lenzi, R.; Frost, P. Unknown primary carcinoma: Natural history and prognostic factors in 657 consecutive patients. J. Clin. Oncol. 1994, 12, 1272-1280.
211. Klein, C.A.; Holzel, D. Systemic cancer progression and tumor dormancy: Mathematical models meet single cell genomics. Cell Cycle 2006, 5, 1788-1798.
212. Sieber, O.M.; Tomlinson, S.R.; Tomlinson, I.P. Tissue, cell and stage specificity of (epi)mutations in cancers. Nat. Rev. Cancer 2005, 5, 649-655.
213. Fialkow, P.J. Clonal origin of human tumors. Annu. Rev. Med. 1979, 30, 135-143.
214. Weinberg, R.A. The Biology of Cancer, 1st ed; Garland Science: New York, NY, USA, 2007; p. 796.
215. Novelli, M.R.; Williamson, J.A.; Tomlinson, I.P.; Elia, G.; Hodgson, S.V.; Talbot, I.C.; Bodmer, W.F.; Wright, N.A. Polyclonal origin of colonic adenomas in an XO/XY patient with FAP. Science 1996, 272, 1187-1190.
216. Leroi, A.M.; Koufopanou, V.; Burt, A. Cancer selection. Nat. Rev. Cancer 2003, 3, 226-231.
217. Diaz-Cano, S.J. Kinetic topographical heterogeneity in follicular thyroid neoplasms and growth patterns. Histopathology 2007, 51, 416-418.
218. Gonzalez-Garcia, I.; Sole, R.V.; Costa, J. Metapopulation dynamics and spatial heterogeneity in cancer. Proc. Natl. Acad. Sci. USA 2002, 99, 13085-13089.
219. Gatenby, R.A.; Silva, A.S.; Gillies, R.J.; Frieden, B.R. Adaptive therapy. Cancer Res. 2009, 69, 4894-4903.
220. Gatenby, R.A.; Vincent, T.L. An evolutionary model of carcinogenesis. Cancer Res. 2003, 63, 6212-6220.
221. Chan, D.A.; Giaccia, A.J. Hypoxia, gene expression, and metastasis. Cancer Metastasis Rev. 2007, 26, 333-339.
222. Evans, S.M.; Hahn, S.M.; Magarelli, D.P.; Koch, C.J. Hypoxic heterogeneity in human tumors: EF5 binding, vasculature, necrosis, and proliferation. Am. J. Clin. Oncol. 2001, 24, 467-472.
223. Martinive, P.; Defresne, F.; Quaghebeur, E.; Daneau, G.; Crokart, N.; Grégoire, V.; Gallez, B.; Dessy, C.; Feron, O. Impact of cyclic hypoxia on HIF-1alpha regulation in endothelial cells--new insights for anti-tumor treatments. FEBS J. 2009, 276, 509-518.
224. Kim, Y.; Lin, Q.; Glazer, P.M.; Yun, Z. Hypoxic tumor microenvironment and cancer cell differentiation. Curr. Mol. Med. 2009, 9, 425-434.
225. Harris, A.L. Hypoxia--a key regulatory factor in tumour growth. Nat. Rev. Cancer 2002, 2, 38-47.
226. Subarsky, P.; Hill, R.P. The hypoxic tumour microenvironment and metastatic progression. Clin. Exp. Metastasis 2003, 20, 237-250.
227. Pouyssegur, J.; Dayan, F.; Mazure, N.M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006, 441, 437-443.
228. Semenza, G.L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 2003, 3, 721-732.
229. Struckmann, K.; Mertz, K.; Steu, S.; Storz, M.; Staller, P.; Krek, W.; Schraml, P.; Moch, H. pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma. J Pathol 2008, 214, 464-471.
230. Keith, B.; Simon, M.C. Hypoxia-inducible factors, stem cells, and cancer. Cell 2007, 129, 465-472.
231. Bos, R.; Zhong, H.; Hanrahan, C.F.; Mommers, E.C.; Semenza, G.L.; Pinedo, H.M.; Abeloff, M.D.; Simons, J.W.; van Diest, P.J.; van der Wall, E. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J. Natl. Cancer Inst. 2001, 93, 309-314.
232. Semenza, G.L. Angiogenesis in ischemic and neoplastic disorders. Annu. Rev. Med. 2003, 54, 17-28.
233. Serrati, S.; Margheri, F.; Fibbi, G.; Di Cara, G.; Minafra, L.; Pucci-Minafra, I.; Liotta, F.; Annunziato, F.; Pucci, M.; Del Rosso, M. Endothelial cells and normal breast epithelial cells enhance invasion of breast carcinoma cells by CXCR-4-dependent up-regulation of urokinase-type plasminogen activator receptor (uPAR, CD87) expression. J. Pathol. 2008, 214, 545-554.
234. Jankowski, K.; Kucia, M.; Wysoczynski, M.; Reca, R.; Zhao, D.; Trzyna, E.; Trent, J.; Peiper, S.; Zembala, M.; Ratajczak, J. et al. Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy. Cancer Res. 2003, 63, 7926-7935.
235. Libura, J.; Drukala, J.; Majka, M.; Tomescu, O.; Navenot, J.M.; Kucia, M.; Marquez, L.; Peiper, S.C.; Barr, F.G.; Janowska-Wieczorek, A. et al. CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood 2002, 100, 2597-2606.
236. Maeda, S.; Shinchi, H.; Kurahara, H.; Mataki, Y.; Maemura, K.; Sato, M.; Natsugoe, S.; Aikou, T.; Takao, S. CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer. Br. J. Cancer 2008, 98, 1389-1397.
237. Brabletz, T.; Jung, A.; Spaderna, S.; Hlubek, F.; Kirchner, T. Opinion: Migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat. Rev. Cancer 2005, 5, 744-749.
238. Kang, Y.; Massague, J. Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell 2004, 118, 277-279.
239. Diaz-Cano, S.J. Re: Pomerance et al. High-level expression, activation, and subcellular localization of p38-MAP kinase in thyroid neoplasms. J. Pathol. 2006, 209, 298-306; J. Pathol. 2006, 210, 133-134.
240. Murphy, P.M. Chemokines and the molecular basis of cancer metastasis. N. Engl. J. Med. 2001, 345, 833-835.
241. Stainier, D. No stem cell is an islet (yet). N. Engl. J. Med. 2006, 354, 521-523.
242. Zlotnik, A. New insights on the role of CXCR4 in cancer metastasis. J. Pathol. 2008, 215, 211-213.
243. DeNardo, D.G.; Johansson, M.; Coussens, L.M. Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev. 2008, 27, 11-18.
244. Hiratsuka, S.; Watanabe, A.; Sakurai, Y.; Akashi-Takamura, S.; Ishibashi, S.; Miyake, K.; Shibuya, M.; Akira, S.; Aburatani, H.; Maru, Y. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat. Cell Biol. 2008, 10, 1349-1355.
245. Bornstein, S.R.; Hornsby, P.J. What can we learn from gene expression profiling for adrenal tumor management? J. Clin. Endocrinol. Metab. 2005, 90, 1900-1902.
246. Garber, M.E.; Troyanskaya, O.G.; Schluens, K.; Petersen, S.; Thaesler, Z.; Pacyna-Gengelbach, M.; van de Rijn, M.; Rosen, G.D.; Perou, C.M.; Whyte, R.I. et al. Diversity of gene expression in adenocarcinoma of the lung. Proc. Natl. Acad. Sci. USA 2001, 98, 13784-13789.
247. Steeg, P.S. New insights into the tumor metastatic process revealed by gene expression profiling. Am. J. Pathol. 2005, 166, 1291-1294.
248. van de Rijn, M.; Rubin, B.P. Gene expression studies on soft tissue tumors. Am. J. Pathol. 2002, 161, 1531-1534.
249. Van'T Veer, L.J.; Paik, S.; Hayes, D.F. Gene expression profiling of breast cancer: A new tumor marker. J. Clin. Oncol. 2005, 23, 1631-1635.
250. Vaupel, P.; Harrison, L. Tumor hypoxia: Causative factors, compensatory mechanisms, and cellular response. Oncologist 2004, 9, 4-9.
251. Pennacchietti, S.; Michieli, P.; Galluzzo, M.; Mazzone, M.; Giordano, S.; Comoglio, P.M. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 2003, 3, 347-361.
252. Kulshreshtha, R.; Davuluri, R.V.; Calin, G.A.; Ivan, M. A microRNA component of the hypoxic response. Cell Death Differ. 2008, 15, 667-671.
253. Ouatas, T.; Salerno, M.; Palmieri, D.; Steeg, P.S. Basic and translational advances in cancer metastasis: Nm23. J. Bioenerg. Biomembr. 2003, 35, 73-79.
254. Salerno, M.; Ouatas, T.; Palmieri, D.; Steeg, P.S. Inhibition of signal transduction by the nm23 metastasis suppressor: Possible mechanisms. Clin. Exp. Metastasis 2003, 20, 3-10.
255. Steeg, P.S. Metastasis suppressors alter the signal transduction of cancer cells. Nat. Rev. Cancer 2003, 3, 55-63.
256. Steeg, P.S.; Ouatas, T.; Halverson, D.; Palmieri, D.; Salerno, M. Metastasis suppressor genes: Basic biology and potential clinical use. Clin. Breast Cancer 2003, 4, 51-62.
257. Wulfkuhle, J.D.; Paweletz, C.P.; Steeg, P.S.; Petricoin, E.F., 3rd; Liotta, L. Proteomic approaches to the diagnosis, treatment, and monitoring of cancer. Adv. Exp. Med. Biol. 2003, 532, 59-68.
258. Diaz-Cano, S.J. Paratumoral gene expression profiles: Promising markers of malignancy in melanocytic lesions. Br. J. Dermatol. 2011, 165, 702-703.
259. Wachsman, W.; Morhenn, V.; Palmer, T.; Walls, L.; Hata, T.; Zalla, J.; Scheinberg, R.; Sofen, H.; Mraz, S.; Gross, K. et al. Noninvasive genomic detection of melanoma. Br. J. Dermatol. 2011, 164, 797-806.
260. Peinado, H.; Lavotshkin, S.; Lyden, D. The secreted factors responsible for pre-metastatic niche formation: Old sayings and new thoughts. Semin. Cancer Biol. 2011, 21, 139-146.
261. György, B.; Szabó, T.G.; Pásztói, M.; Pál, Z.; Misják, P.; Aradi, B.; László, V.; Pállinger, E.; Pap, E.; Kittel, A. et al. Membrane vesicles, current state-of-the-art: Emerging role of extracellular vesicles. Cell. Mol. Life Sci. 2011, 68, 2667-2688.
262. Valadi, H.; Ekstrom, K.; Bossios, A.; Sjostrand, M.; Lee, J.J.; Lotvall, J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007, 9, 654-659.
263. Mathivanan, S.; Ji, H.; Simpson, R.J. Exosomes: Extracellular organelles important in intercellular communication. J. Proteomics 2010, 73, 1907-1920.
264. Hendrix, A.; Westbroek, W.; Bracke, M.; De Wever, O. An ex(o)citing machinery for invasive tumor growth. Cancer Res. 2010, 70, 9533-9537.
265. Whiteside, T.L.; Mandapathil, M.; Szczepanski, M.; Szajnik, M. Mechanisms of tumor escape from the immune system: Adenosine-producing Treg, exosomes and tumor-associated TLRs. Bull. Cancer 2011, 98, E25-E31.
266. Esteller, M. Non-coding RNAs in human disease. Nat. Rev Genet. 2011, 12, 861-874.
267. Corcoran, C.; Friel, A.M.; Duffy, M.J.; Crown, J.; O'Driscoll, L. Intracellular and extracellular microRNAs in breast cancer. Clin. Chem. 2011, 57, 18-32.
268. Krutovskikh, V.A.; Herceg, Z. Oncogenic microRNAs (OncomiRs) as a new class of cancer biomarkers. Bioessays 2010, 32, 894-904.
269. Curtin, J.A.; Fridlyand, J.; Kageshita, T.; Patel, H.N.; Busam, K.J.; Kutzner, H.; Cho, K.H.; Aiba, S.; Bröcker, E.B.; LeBoit, P.E. et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 2005, 353, 2135-2147.
270. Lee, J.H.; Choi, J.W.; Kim, Y.S. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: A meta-analysis. Br. J. Dermatol. 2011, 164, 776-784.
271. Guo, Y.; Feng, Y.; Trivedi, N.S.; Huang, S. Medusa structure of the gene regulatory network: Dominance of transcription factors in cancer subtype classification. Exp. Biol. Med. (Maywood) 2011, 236, 628-636.
272. Guo, Z.; Wu, F.; Asplund, A.; Hu, X.; Mazurenko, N.; Kisseljov, F.; Pontén, J.; Wilander, E. Analysis of intratumoral heterogeneity of chromosome 3p deletions and genetic evidence of polyclonal origin of cervical squamous carcinoma. Mod. Pathol. 2001, 14, 54-61.
273. Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 2008, 358, 1148-1159.
274. Feinberg, A.P. The epigenetics of cancer etiology. Semin. Cancer Biol. 2004, 14, 427-432.
275. Eden, A.; Gaudet, F.; Waghmare, A.; Jaenisch, R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 2003, 300, 455.
276. Gaudet, F.; Hodgson, J.G.; Eden, A.; Jackson-Grusby, L.; Dausman, J.; Gray, J.W.; Leonhardt, H.; Jaenisch, R. Induction of tumors in mice by genomic hypomethylation. Science 2003, 300, 489-492.
277. Karpf, A.R.; Matsui, S. Genetic disruption of cytosine DNA methyltransferase enzymes induces chromosomal instability in human cancer cells. Cancer Res. 2005, 65, 8635-8639.
278. Bestor, T.H. Transposons reanimated in mice. Cell 2005, 122, 322-325.
279. Esteller, M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat. Rev. Genet. 2007, 8, 286-298.
280. Esteller, M.; Herman, J.G. Generating mutations but providing chemosensitivity: The role of O6-methylguanine DNA methyltransferase in human cancer. Oncogene 2004, 23, 1-8.
281. Nieto, M.; Samper, E.; Fraga, M.F.; Gonzalez de Buitrago, G.; Esteller, M.; Serrano, M. The absence of p53 is critical for the induction of apoptosis by 5-aza-2'-deoxycytidine. Oncogene 2004, 23, 735-743.
282. Agrelo, R.; Cheng, W.H.; Setien, F.; Ropero, S.; Espada, J.; Fraga, M.F.; Herranz, M.M.F.; Sanchez-Cespedes, M.; Artiga, M.J. et al. Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proc. Natl. Acad. Sci. USA 2006, 103, 8822-8827.
283. Ballestar, E.; Paz, M.F.; Valle, L.; Wei, S.; Fraga, M.F.; Espada, J.; Cigudosa, J.C.; Huang, T.H.; Esteller, M. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J. 2003, 22, 6335-6345.
284. Fraga, M.F.; Ballestar, E.; Villar-Garea, A.; Boix-Chornet, M.; Espada, J.; Schotta, G.; Bonaldi, T.; Haydon, C.; Ropero, S.; Petrie, K. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 2005, 37, 391-400.
285. He, L.; Hannon, G.J. MicroRNAs: Small RNAs with a big role in gene regulation. Nat. Rev. Genet. 2004, 5, 522-531.
286. Lujambio, A.; Ropero, S.; Ballestar, E.; Lujambio, A.; Ropero, S.; Ballestar, E.; Fraga, M.F.; Cerrato, C.; Setién, F.; Casado, S. et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 2007, 67, 1424-1429.
287. Nakamura, T.; Kuwai, T.; Kitadai, Y.; Sasaki, T.; Fan, D.; Coombes, K.R.; Kim, S.J.; Fidler, I.J. Zonal heterogeneity for gene expression in human pancreatic carcinoma. Cancer Res. 2007, 67, 7597-7604.
288. Shipitsin, M.; Campbell, L.L.; Argani, P.; Weremowicz, S.; Bloushtain-Qimron, N.; Yao, J.; Nikolskaya, T.; Serebryiskaya, T.; Beroukhim, R.; Hu, M. et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 2007, 11, 259-273.
289. Tomlinson, I.P.; Lambros, M.B.; Roylance, R.R. Loss of heterozygosity analysis: Practically and conceptually flawed? Genes Chromosomes Cancer 2002, 34, 349-353.
290. Califano, J.; van der Riet, P.; Westra, W.; Nawroz, H.; Clayman, G.; Piantadosi, S.; Corio, R.; Lee, D.; Greenberg, B.; Koch, W. et al. Genetic progression model for head and neck cancer: Implications for field cancerization. Cancer Res. 1996, 56, 2488-2492.
291. Parsons, D.W.; Jones, S.; Zhang, X.; Lin, J.C.-H.; Leary, R.J.; Angenendt, P.; Mankoo, P.; Carter, H.; Siu, I.-M.; Gallia, G.L. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008, 321, 1807-1812.
292. Wood, L.D.; Parsons, D.W.; Jones, S.; Lin, J.; Sjöblom, T.; Leary, R.J.; Shen, D.; Boca, S.M.; Barber, T.; Ptak, J. et al. The genomic landscapes of human breast and colorectal cancers. Science 2007, 318, 1108-1113.
293. Siegmund, K.D.; Marjoram, P.; Woo, Y.J.; Tavare, S.; Shibata, D. Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers. Proc. Natl. Acad. Sci. USA 2009, 106, 4828-4833.
294. Diaz-Cano, S. PCR-based alternative for diagnosis of immunoglobulin heavy chain gene rearrangement: Principles, practice, and polemics. Diagn. Mol. Pathol. 1996, 5, 3-9.
295. Brady, S.P.; Magro, C.M.; Diaz-Cano, S.J.; Wolfe, H.J. Analysis of clonality of atypical cutaneous lymphoid infiltrates associated with drug therapy by PCR/DGGE. Hum. Pathol. 1999, 30, 130-136.
296. Campbell, P.J.; Pleasance, E.D.; Stephens, P.J.; Dicks, E.; Rance, R.; Goodhead, I.; Follows, G.A.; Green, A.R.; Futreal, P.A.; Stratton, M.R. Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing. Proc. Natl. Acad. Sci. USA 2008, 105, 13081-13086.
297. Mullighan, C.G.; Phillips, L.A.; Su, X.; Ma, J.; Miller, C.B.; Shurtleff, S.A.; Downing, J.R. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008, 322, 1377-1380.
298. Panzer-Grumayer, E.R.; Cazzaniga, G.; van der Velden, V.H.; del Giudice, L.; Peham, M.; Mann, G.; Eckert, C.; Schrauder, A.; Germano, G.; Harbott, J. et al. Immunogenotype changes prevail in relapses of young children with TEL-AML1-positive acute lymphoblastic leukemia and derive mainly from clonal selection. Clin. Cancer Res. 2005, 11, 7720-7727.
299. Teixeira, M.R.; Pandis, N.; Bardi, G.; Andersen, J.A.; Heim, S. Karyotypic comparisons of multiple tumorous and macroscopically normal surrounding tissue samples from patients with breast cancer. Cancer Res. 1996, 56, 855-859.
300. Teixeira, M.R.; Pandis, N.; Bardi, G.; Andersen, J.A.; Mitelman, F.; Heim, S. Clonal heterogeneity in breast cancer: Karyotypic comparisons of multiple intra- and extra-tumorous samples from 3 patients. Int. J. Cancer 1995, 63, 63-68.
301. Giaretti, W.; Monaco, R.; Pujic, N.; Rapallo, A.; Nigro, S.; Geido, E. Intratumor heterogeneity of K-ras2 mutations in colorectal adenocarcinomas: Association with degree of DNA aneuploidy. Am. J. Pathol. 1996, 149, 237-245.
302. Coons, S.W.; Johnson, P.C.; Shapiro, J.R. Cytogenetic and flow cytometry DNA analysis of regional heterogeneity in a low grade human glioma. Cancer Res. 1995, 55, 1569-1577.
303. Kallioniemi, O.P. Comparison of fresh and paraffin-embedded tissue as starting material for DNA flow cytometry and evaluation of intratumor heterogeneity. Cytometry 1988, 9, 164-169.
304. Lage, J.M.; Leamon, J.H.; Pejovic, T.; Hamann, S.; Lacey, M.; Dillon, D.; Segraves, R.; Vossbrinck, B.; González, A.; Pinkel, D. et al. Whole genome analysis of genetic alterations in small DNA samples using hyperbranched strand displacement amplification and array-CGH. Genome Res. 2003, 13, 294-307.
305. Leith, J.T.; Michelson, S.; Faulkner, L.E.; Bliven, S.F. Growth properties of artificial heterogeneous human colon tumors. Cancer Res. 1987, 47, 1045-1051.
306. Farber, L.; Efrati, E.; Elkin, H.; Peerless, Y.; Sabo, E.; Ben-Izhak, O.; Hershkovitz, D. Molecular morphometric analysis shows relative intra-tumoural homogeneity for KRAS mutations in colorectal cancer. Virchows Arch. 2011, 459, 487-493.
307. Kuwai, T.; Nakamura, T.; Kim, S.J.; Sasaki, T.; Kitadai, Y.; Langley, R.R.; Fan, D.; Hamilton, S.R.; Fidler, I.J. Intratumoral heterogeneity for expression of tyrosine kinase growth factor receptors in human colon cancer surgical specimens and orthotopic tumors. Am. J. Pathol. 2008, 172, 358-366.
308. Inda, M.M.; Bonavia, R.; Mukasa, A.; Narita, Y.; Sah, D.W.Y.; Vandenberg, S.; Brennan, C.; Johns, T.G.; Bachoo, R.; Hadwiger, P. et al. Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev. 2010, 24, 1731-1745.
309. Konishi, N.; Hiasa, Y.; Matsuda, H.; Tao, M.; Tsuzuki, T.; Hayashi, I.; Kitahori, Y.; Shiraishi, T.; Yatani, R.; Shimazaki, J. et al. Intratumor cellular heterogeneity and alterations in ras oncogene and p53 tumor suppressor gene in human prostate carcinoma. Am. J. Pathol. 1995, 147, 1112-1122.
310. Maley, C.C.; Reid, B.J.; Forrest, S. Cancer prevention strategies that address the evolutionary dynamics of neoplastic cells: Simulating benign cell boosters and selection for chemosensitivity. Cancer Epidemiol. Biomarkers Prev. 2004, 13, 1375-1384.
311. Cottu, P.H.; Asselah, J.; Lae, M.; Pierga, J.Y.; Diéras, V.; Mignot, L.; Sigal-Zafrani, B.; Vincent-Salomon, A. Intratumoral heterogeneity of HER2/neu expression and its consequences for the management of advanced breast cancer. Ann. Oncol. 2008, 19, 595-597.