Abstract
This article discusses the role of carcinoembryonic antigen (CEA) as a facilitator of the inflammatory response and its effect on colorectal cancer hepatic metastasis. Colorectal cancer accounts for 11% of all cancers in the United States and the majority of deaths are associated with liver metastasis. If left untreated, median survival is only six to 12 months. Resection of liver metastases offers the only chance for cure. Of the small number of patients who have operable cancer most will have further tumor recurrence. The molecular mechanisms associated with colorectal cancer metastasis to the liver are largely unknown. However CEA production has been shown both clinically and experimentally to be a factor in an increased metastatic potential of colorectal cancers to the liver. CEA also has a role in protecting tumor cells from the effects of anoikis and this affords a selective advantage for tumor cell survival in the circulation. CEA acts in the liver through its interaction with its receptor (CEAR), a protein that is related to the hnRNP M family of RNA binding proteins. In the liver CEA binds with hnRNP M on Kupffer cells and causes activation and production of pro- and anti-inflammatory cytokines including IL-1, IL-10, IL-6 and TNF-α. These cytokines affect the up-regulation of adhesion molecules on the hepatic sinusoidal endothelium and protect the tumor cells against cytotoxicity by nitric oxide (NO) and other reactive oxygen radicals. HnRNP M signaling in Kupffer cells appears to be controlled by beta-adrenergic receptor activation. The cells will respond to the β-adrenergic receptor agonist terbutaline resulting in reduced TNF-α and increased IL-10 and IL-6 production following CEA activation. This has implications for the control of tumor cell implantation and survival in the liver.
Similar content being viewed by others
References
Siegel R, Ward E, Brawley O et al (2009) Cancer statistics, 2011. CA Cancer J Clin 61:212–236
Zak Y, Moore HG, Ghosh BC (2007) Patterns of recurrence of colorectal cancer. J Surg Oncol 97:1–2
Millikan KW, Staren ED, Doolas A (1997) Invasive therapy of metastatic colorectal cancer to the liver. Surg Clin North Am 77:27–28
Bird NC, Mangnall D, Majeed AW (2006) Biology of colorectal liver metastases: a review. J Surg Oncol 94:68–80
Fusai G, Davidson BR (2003) Management of colorectal liver metastases. Colorectal Dis 5:2–23
Topal B, Aerts JL, Roskams T et al (2005) Cancer cell dissemination during curative surgery for colorectal liver metastases. Eur J Surg Onc 31:506–511
Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion and metastasis. Cell 124:263–266
Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612
Dittmar T, Heyder C, Gloria-Maercker E et al (2008) Adhesion molecules and chemokines: the navigation system for circulating tumor (stem) cells to metastasize in an organ specific manner. Clin Exp Metastasis 25:11–32
Eccles SA (2005) Targeting key steps in metastatic tumor progression. Curr Opin Genet Dev 15:77–86
Wang W, Goswami S, Dahai E et al (2005) Tumor cells caught in the act of invading: their strategy for enhanced cell motility. Trends Cell Biol 15:138–145
Thompson E, Newgreen DF (2005) Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res 65:5991–5995
Tse JC, Kalluri R (2007) Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 101:816–829
Yang J, Mani SA, Weinberg RA (2006) Exploring a new twist on tumor metastasis. Cancer Res 66:4549–4552
Ludwig T (2005) Local proteolytic activity in tumor cell invasion and metastasis. BioEssays 27:1181–1191
Tarin D (2005) The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65:5996–6001
Christensen JJ, Rajasekaran AK (2006) Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66:8319–8326
Hugo H, Ackland ML, Buck T et al (2007) Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 213:374–383
Kim S, Takahashi H, Lin WW (2009) Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457:102–106
Wagner HE, Toth CA, Steele GD et al (1992) Invasive and metastatic potential of human colorectal cancer cell lines: relationship to cellular differentiation and carcinoembryonic antigen production. Clin Exp Metastasis 10:25–31
Paget S (1889) The distribution of secondary growth in cancer of the breast. Lancet 1:571–573
Macarthur M, Hold GL, El-Omar GM (2004) Inflammation and cancer. II. Role of chronic inflammation and cytokine polymorphisms in the pathogenesis of gastrointestinal malignancy. Am J Physiol 286:G515–G520
Ellerman JE, Brown CK, de Vera M et al (2007) Masquerader: high mobility box-1 and cancer. Clin Cancer Res 13:2836–2848
Gebhart C, Nemeth J, Angel P et al (2006) S100A8 and S100A9 in inflammation and cancer. Biochem Pharmacol 72:1622–1631
Nicolson GL (1988) Cancer metastasis: tumor cell and host organ properties important to metastasis to specific secondary sites. Biochim Biophys Acta 948:175–224
Nicolson GL (1988) Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev 7:143–188
West NP, Dattani M, McShane P et al (2010) The proportion of tumor cells is an independent predictor for survival in colorectal cancer patients. Br J Cancer 102:1519–1523
Solakoglu O, Maierhofer C, Lahr G et al (2002) Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proc Natl Acad Sci USA 99:2246–2251
Hess KR, Varadhachary GR, Taylor SH (2006) Metastatic patterns in adenocarcinoma. Cancer 106:1624–1633
Lindmann F, Schlimok G, Dirschedl P et al (1992) Prognostic significance of micrometastatic tumor cells in bone marrow of colorectal cancer patients. Lancet 340:685–689
Bonneheim DC, Petrelli NJ, Herrera L et al (1986) Osseous metastases from colorectal carcinoma. Am J Surg 151:457–459
Talbot RW, Irvine B, Dowd GS, Northover JM (1989) Bone metastases in carcinoma of the rectum: a clinical and pathological review. Eur J Surg Oncol 15:449–452
Lin EY, Nguyen AV, Russell RG (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193:727–739
Sunderkotter C, Goebeler M, Schulze-Osthoff K et al (1990) Macrophage derived angiogenesis factors. Pharmacol Ther 51:195–216
Lewis CE, Leek R, Harris A et al (1995) Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J Leukoc Biol 57:747–781
Toth CA (1992) Carcinoembryonic antigen binding proteins on elicited peritoneal macrophages. J Leukoc Biol 51:466–471
Galon J, Fridman WH, Pages F (2007) The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 67:1883–1886
Gold P, Freedman SO (1965) Specific carcinoembryonic antigens of the human digestive system. J Exp Med 122:467–481
Hammarström S (1999) The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 9:67–81
Beauchemin N, Draber P, Dveksler G et al (1999) Redefined nomenclature for members of the carcinoembryonic antigen gene family. Exp Cell Res 252:243–249
Thomas P, Toth CA, Saini KS et al (1990) The structure, metabolism and function of the carcinoembryonic antigen gene family. Biochim Biophys Acta 1032:177–189
Thompson JA, Grunert F, Zimmermann W (1991) Carcinoembryonic antigen gene family: molecular biology and clinical perspectives. J Clin Lab Anal 5:344–366
Schrewe H, Thompson J, Bona M et al (1990) Cloning of the complete gene for carcinoembryonic antigen: analysis of its promoter indicates a region conveying cell type-specific expression. Mol Cell Biol 10:2738–2748
Jessup JM, Thomas P (1998) CEA and metastasis: a facilitator of site specific metastasis. In: Stanners C (ed) Cell adhesion and communication mediated by the CEA family: basic and clinical perspectives. Harwood Academic Publishers, Amsterdam, Netherlands, pp 195–222
Irvine T, Scott M, Clark CI (2007) A small raise in CEA is sensitive for recurrence after surgery for colorectal cancer. Colorectal Dis 9:527–531
Stout RL, Fulks M, Dolan VF et al (2007) Increased mortality associated with elevated carcinoembryonic antigen in insurance applicants. J Insur Med 39:251–258
Kelly KJ, Wong J, Gladdy R et al (2009) Prognostic impact of RT-PCR based detection of peritoneal micro metastases in patients with pancreatic cancer undergoing curative resection. Ann Surg Oncol 16:3333–3339
Maraqa L, Cummings M, Peter MB et al (2008) Carcinoembryonic antigen cell adhesion molecule 6 predicts breast cancer recurrence following adjuvant tamoxifen. Clin Cancer Res 14:405–411
Jantscheff P, Terraciano L, Lowy A et al (2003) Expression of CEACAM6 in resectable colorectal cancer: a factor of independent prognostic significance. J Clin Oncol 21:3638–3646
Goldstein MJ, Mitchell EP (2005) Carcinoembryonic antigen in the staging and follow up of patients with colorectal cancer. Cancer Invest 23:338–351
Koppe MJ, Bleichrodt RP, Oyen WJG (2005) Radioimmunotherapy and colorectal cancer. Br J Surg 92:264–276
Ilantzis C, DeMarte L, Screaton RA et al (2002) Deregulated expression of the human tumor marker CEA and CEA family member CEACAM6 disrupts tissue architecture and blocks colonocyte differentiation. Neoplasia 4:151–163
Ilantzis C, Jothy S, Alpert LC et al (1997) Cell surface levels of human carcinoembryonic antigen are inversely correlated with colonocyte differentiation in colon carcinogenesis. Lab Invest 76:703–716
Leusch HG, Drzeniek Z, Hefta SA (1991) The putative role of members of the CEA-gene family (CEA, NCA an BGP) as ligands for the bacterial colonization of different human epithelial tissues. Zentralbl Bakteriol 275:118–122
Leusch HG, Hefta SA, Drzeniek Z et al (1990) Escherichia coli of human origin binds to carcinoembryonic antigen (CEA) and non-specific cross reacting antigen (NCA). FEBS Lett 261:405–409
Virji M, Watt SM, Barker S et al (1996) The N-domain of the human CD66a adhesion molecule is a target for Opa proteins of Neisseria meningitides and Neisseria gonorrhea. Mol Microbiol 22:929–939
Dveksler GS, Dieffenbach CW, Cardellichio CB (1993) Several members of the mouse carcinoembryonic antigen-related glycoprotein family are functional receptors for the coronavirus mouse hepatitis virus-A59. J Virol 67:1–8
Tan K, Zelus BD, Meijers R, Liu JH (2002) Crystal structure of murine sCEACAM1a[1, 4]: a coronavirus receptor in the CEA family. EMBO J 21:2076–2086
Thomas P, Zamcheck N (1983) The role of the liver in the clearance and excretion of circulating carcinoembryonic antigen (CEA). Dig Dis Sci 28:216–224
O’Brien MJ, Bronstein B, Zamcheck N et al (1980) Cholestasis and hepatic metastases: a factor contributing to very high plasma carcinoembryonic antigen (CEA) elevations. J Natl Cancer Inst 64:1291–1294
Paschos KA, Majeed AW, Bird NC (2010) Role of Kupffer cells in the outgrowth of colorectal cancer liver metastases. Hepatol Res 40:83–94
Bajenova OV, Zimmer R, Stolper E et al (2001) HnRNP M4 is a receptor for carcinoembryonic antigen in Kupffer cells. J Biol Chem 276:31067–31073
Bajenova O, Stolper E, Gapon S et al (2003) Surface expression of HnRNP M4 nuclear protein on Kupffer cells relates to its function as a carcinoembryonic antigen receptor. Exp Cell Res 292:282–291
Datar KV, Dreyfus G, Swanson MS (1993) The human HNRNP M proteins: identification of a methionine arginine rich repeat motif in ribonucleoproteins. Nucleic Acids Res 21:439–446
Blanck I, Perrin C, Mziaut H (1994) Molecular-cloning, cDNA analysis, and localization of a monomer of the N-acetylglucosamine-specific receptor of the thyroid, NAGR1, to chromosome 19p13.3–13.2. Genomics 21:18–26
Blanck I, Perrin C, Mziaut H (1995) Erratum. Genomics 27:561
Gangopadhyay A, Thomas P (1996) Processing of carcinoembryonic antigen by Kupffer cells: recognition of a penta-peptide sequence. Arch Biochem Biophys 334:151–157
Tosi M, Duponchel C, Meo T et al (1987) Complete cDNA sequence of human complement Cls and close physical linkage of the homologous genes Cls and Clr. Biochemistry 26:8516–8524
Zimmer R, Thomas P (2001) Mutations in the carcinoembryonic antigen gene in colorectal cancer patients: implications on liver metastasis. Cancer Res 61:2822–2826
Ordonez C, Screaton RA, Ilantizis C (2000) Human carcinoembryonic antigen functions as a general inhibitor of anoikis. Cancer Res 60:3419–3424
Soeth E, Wirth T, List HJ et al (2001) Controlled ribozyme targeting demonstrates an anti-apoptotic effect of carcinoembryonic antigen in HT-29 colon cancer cells. Clin Cancer Res 7:2022–2030
Laguinge L, Bajenova O, Bowden E et al (2005) Nuclear protein hn RNP M4 interacts with CEA and might mediate signal transduction activity of CEA in HT29 colon cancer cells. Anticancer Res 25:23–32
Samara RN, Laguinge LM, Jessup JM (2007) Carcinoembryonic antigen inhibits anoikis in colorectal carcinoma cells by interfering with TRAIL-R2 (DR5) signaling. Cancer Res 67:4774–4782
Kim JH, Hahm B, Kim YK (2000) Protein-protein interaction among hnRNPs shuttling between nucleus and cytoplasm. J Mol Biol 298:395–405
Dreyfuss G, Kim VN, Kataoka N (2002) Messenger-RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol 3:195–205
Venables JP, Koh C-S, Froehlich U et al (2008) Multiple and specific mRNA processing targets for the major human hnRNP proteins. Mol Cell Biol 28:6033–6043
Carpenter B, MacKay C, Alnabulsi A et al (2005) The roles of heterogeneous nuclear ribonucleoproteins in tumor development and progression. Biochim Biophys Acta 1765:85–100
Khotin M, Turoverova L, Aksenova V et al (2010) Proteomic analysis of ACTN-4interacting proteins reveals its putative involvement in mRNA metabolism. Biochem Biophys Res Commun 395:192–196
Thomas P, Ivanov G, Adejuyigbe O et al (2007) A unique Kupffer cell receptor system: Involvement in colorectal cancer metastasis to the liver. In: Proceedings of the 7th world congress on trauma, shock, inflammation and sepsis. Monduzzi Editore international proceedings, pp 157–161
Schumann D, Chen CJ, Kaplan B, Shively JE (2001) Carcinoembryonic antigen cell adhesion molecule 1 directly associates with cytoskeletal proteins actin and tropomyosin. J Biol Chem 276:47421–47433
Guil S, Caceres JF (2007) The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat Struct Mol Biol 14:491–596
Hovhannisyan RH, Carstens RP (2007) Heterogenous ribonucleoprotein M is a splicing regulatory protein that can enhance or silence splicing of alternatively spliced exons. J Biol Chem 282:36265–36274
Dery KJ, Gaur S, Gencheva M et al (2011) Mechanistic control of carcinoembryonic antigen related cell adhesion molecule-1 (CEACAM-1) splice isoforms by the heterogeneous nuclear ribonuclear proteins hnRNP L, hnRNP A1 and hnRNP M. J Biol Chem 285:16039–16051
Han SP, Tang YH, Smith R (2010) Functional diversity of the hnRNPs: past present and perspectives. Biochem J 430:379–392
Ganguly A, Yeltsin E, Robbins J (2003) Identification of a carcinoembryonic antigen binding protein on monocytes. Biochem Biophys Res Commun 311:319–323
Hernandez A, Smith F, Wang Q (2000) Assessment of differential gene expression patterns in human colon cancers. Ann Surg 232:576–585
Zimmer R, Thomas P (2002) Expression profiling and interferon-beta (INF-B) regulation of metastasis in colorectal cancer cells. Clin Exp Metastasis 19:541–550
Bertucci F, Salas S, Eyesteries S et al (2004) Gene expression profiling of colon cancer by DNA microarrays and correlation with histochemical parameters. Oncogene 23:1377–1391
Oue N, Hamai Y, Mitani Y (2004) Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression. Cancer Res 64:2397–2405
Saha S, Bardelli A, Buckhaults P et al (2001) A phosphatase associated with metastasis of colorectal cancer. Science 294:1343–1346
Tibbetts LM, Doremus CM, Tzanakakis GN et al (1993) Liver metastases with 10 human colon carcinoma cell lines in nude mice and association with carcinoembryonic antigen production. Cancer 71:315–321
Hostetter RB, Augustus LB, Mankarious R et al (1990) Carcinoembryonic antigen as a selective enhancer of colorectal cancer metastases. J Natl Cancer Inst 82:380–385
Thomas P, Gangopadhyay A, Steele G et al (1995) The effect of transfection of the CEA gene on the metastatic behavior of the human colorectal cancer cell line MIP-101. Cancer Lett 92:59–66
Hashino J, Fukada Y, Oikawa S et al (1994) Metastatic potential on human colorectal carcinoma SW1222 cells transfected with cDNA encoding carcinoembryonic antigen. Clin Exp Metastasis 12:324–328
Jessup JM, Petrick AT, Toth CA et al (1993) Carcinoembryonic antigen: enhancement of liver colonization through retention of human colorectal carcinoma cells. Br J Cancer 67:464–470
Langley RR, Fidler IJ (2007) Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocrine Rev 28:297–321
Kobayashi H, Boelte KC et al (2007) Endothelial cell adhesion molecules and cancer progression. Curr Med Chem 14:377–386
Gangopadhyay A, Bajenova O, Kelly TM et al (1996) Carcinoembryonic antigen induces cytokine expression in Kupffer cells; implications for hepatic metastasis from colon cancer. Cancer Res 56:4805–4810
Minami S, Furui J, Kanematsu T (2001) Role of carcinoembryonic antigen in the progression of colon cancer cells that express carbohydrate antigen. Cancer Res 61:2732–2735
Edmiston K, Gangopadhyay A, Shoji Y et al (1997) In vivo induction of murine cytokine production by carcinoembryonic antigen. Cancer Res 57:4432–4436
Tobi M, Kim M, Zimmer R et al (2011) A model of inhibition of liver metastasis: The cotton top tamarin (Saguinus Oedipus). Dig Dis Sci 56:397–405
Thomas P, Hayashi H, Zimmer R et al (2004) Regulation of cytokine production in carcinoembryonic antigen stimulated Kupffer cells by β2-adrenergic receptors. Cancer Lett 209:251–257
Miska M, Wu RQ, Zhou M et al (2005) Sympathetic endotoxicity in sepsis: pro-inflammatory priming of macrophages by norepinephrine. Front Biosci 10:2217–2229
Subervile S, Bellocq A, Foqueray B et al (1996) Regulation of IL-10 production by beta-adrenergic agonists. Eur J Immunol 26:2601–2605
Izeboud CA, Mocking JAJ, Monshouwer M (1999) Participation of beta-adrenergic receptors on macrophages in modulation of LPS induced cytokine release. J Recep Sig Trans Res 19:191–202
Brenner S, Prosch S, Schenke-Layland K et al (2003) cAMP induced interleukin-10 promoter activation depends on CCAAT/enhancer binding protein expression and monocytic differentiation. J Biol Chem 278:5597–5604
Platzer C, Meisel C, Vogt K (1995) Up-regulation of monocytic IL-10 by tumor necrosis factor alpha and cAMP elevating drugs. Int Immunol 7:517–523
Strassmann G, Patilkota V, Fikelman F (1994) Evidence for the involvement of interleukin-10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. J Exp Med 180:2365–2370
Blaxall BC, Pellett AC, Wu SC et al (2000) Purification and characterization of beta-adrenergic receptor mRNA binding proteins. J Biol Chem 275:4290–4297
Gangopadhyay A, Lazure DA, Thomas P (1998) Adhesion of colorectal carcinoma cells to the endothelium is mediated by cytokines from CEA stimulated Kupffer cells. Clin Exp Metastasis 16:703–712
Yamamoto N, Sakai F, Yamakazi H et al (1997) FR167653 a dual inhibitor of interleukin-1 and tumor necrosis factor-α ameliorates endotoxin-induced shock. Eur J Pharmacol 327:169–175
Khatib AM, Auguste P, Fallavollita L et al (2005) Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. Am J Pathol 167:749–759
Khatib AM, Fallavollita L, Wancewicz EV et al (2002) Inhibition of hepatic endothelial E-selectin expression by C-raf antisense oligonucleotides blocks colorectal carcinoma liver metastasis. Cancer Res 62:5393–5398
Jessup JM, Battle P, Waller H (1999) Reactive nitrogen and oxygen radicals formed during hepatic ischemia-reperfusion kill weakly metastatic colorectal cancer cells. Cancer Res 59:1825–1829
Jessup JM, Samara R, Battle P et al (2004) Carcinoembryonic antigen promotes tumor cell survival in liver through an IL-10-dependent pathway. Clin Exp Metastasis 21:709–717
Jessup JM, Laguinge L, Lin S et al (2004) Carcinoembryonic antigen induction of IL-10 and IL-6 inhibits hepatic ischemic/reperfusion injury to colorectal carcinoma cells. Int J Cancer 111:332–337
Kokkonen N, Ulibarri IF, Kaupilla A et al (2007) Hypoxia upregulates carcinoembryonic antigen expression in cancer cells. Int J Cancer 121:2443–2450
Ashizawa T, Okada R, Suzuki Y et al (2006) Study of interleukin-6 in the spread of colorectal cancer: the diagnostic significance of IL-6. Acta Med Okayama 60:325–330
Siragusa T, Miller AR, Belluco C et al (2000) The role of circulating cytokines in colorectal carcinoma. Int J Clin Oncol 5:217–228
Nakagoe T, Tsuji T, Sawai K et al (2003) The relationship between circulating interleukin-6 and carcinoembryonic antigen in patients with colorectal cancer. Anticancer Res 23:3561–3567
Ashizawa T, Aoki T, Sumi T et al (2002) The study of hepatocytes growth factor in the spreading of colorectal cancer: the clinical role of HGF in Dukes’ classification. Jpn J Gastroenterol Surg 35:480–486
Talmadge JE, Fidler IJ (2010) The biology of cancer metastasis: historical perspective. Cancer Res 70:5649–5669
Li Y, Hong C, Zhongxian J et al (2010) Carcinoembryonic antigen interacts with TGF-β Receptor and inhibits TGF-β signaling in colorectal cancers. Cancer Res 70:8159–8168
Huh JW, Oh BR, Kim HR, Kim YJ (2010) Preoperative carcinoembryonic antigen level as an independent prognostic factor in potentially curative colon cancer. J Surg Oncol 101:396–400
Ballin M, Pelina MD, Farina AR et al (1992) Thorgeirsson UP effect of phorbol ester and cytokines on matrix metalloproteinase and tissue inhibitor of metalloproteinase expression in tumor and normal-cell lines. Invasion Metastasis 12:168–184
Westermarck J, Kahari VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13:781–792
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Thomas, P., Forse, R.A. & Bajenova, O. Carcinoembryonic antigen (CEA) and its receptor hnRNP M are mediators of metastasis and the inflammatory response in the liver. Clin Exp Metastasis 28, 923–932 (2011). https://doi.org/10.1007/s10585-011-9419-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10585-011-9419-3