Abstract
We here summarize the current view of molecular mechanisms involved in the dissemination process of colorectal cancer cells to the liver as deduced from preclinical models. We focus on molecular aspects of the current understanding of the biology of liver metastases formation and survival, both being crucial for identification and validation of possible therapeutic targets and review the latest findings elucidating some features of the liver as a metastatic niche. In more detail, we outline the role of proteases and of major pathways such asc-MET signaling and its modulation by factors such as MACC1 and TIMP1, as well as Notch and TGFβ signaling. The relevance of these signalling pathways during tumor-stroma interactions in this context will be addressed. In addition, the functional role and validation of targets such as PRL3, Trop-2, L1CAM, S100A4, S100P, CD133, LIPC, and APOBEC3G are summarized.
Similar content being viewed by others
References
Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170
Velculescu VE, Vogelstein B, Kinzler KW (2000) Analysing uncharted transcriptomes with SAGE. Trends Genet 16:423–425
Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361:2449–2460
Hölzl D, Eckel R, Engel J (2009) Colorectal cancer metastasis. Frequency, prognosis and consequences. Chirurg 80:331–340
Hess KR, Varadhachary GR, Taylor SH, Wei W, Raber MN, Lenz R, Abbruzzese JL (2006) Metastatic patterns in adenocarcinoma. Cancer 106:1624–1633
Wan L, Pantel K, Kang Y (2013) Tumor metastasis: moving new biological insights into the clinic. Nat Med 19:1450–1564
Deneve E, Rietdorf S, Ramos J et al (2013) Capture of viable circulating tumor cells in the liver of colorectal cancer patients. Clin Chem 59:1384–1392
MacDonald IC, Groom AC, Chambers AF (2002) Cancer spread and micrometastasis development: quantitative approaches for in vivo models. BioEssays 24:885–893
Padget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 1:571–573
Sceneay J, Smith MJ, Möller H (2013) The pre-metastatic niche: finding common ground. Cancer Metastasis Rev 32:449–464
Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284
Zeisberg M, Neilson EG (2009) Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119:1429–1437
Brabletz T, Jung A, Hermann K, Günther K, Hohenberger W, Kirchner T (1998) Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract 194:701–704
Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA, Knuechel R, Kirchner T (2001) Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 98:10356–10361
Kirchner T, Brabletz T (2000) Patterning and nuclear beta-catenin expression in the colonic adenoma-carcinoma sequence. Analogies with human gastrulation. Am J Pathol 157:1113–1121
Placke T, Kopp HG, Salih HR (1996) The wolf in sheeps clothing: platelet derived “pseudo-self” impairs cancer cell “missing self” recognition by NK cells. Oncoimmunology 1:557–559
Bayon LG, Izquierdo MA, Sirovich I, van Rooijen N, Beelen RH, Meijer S (1996) Role of Kupffer cells in arresting circulating tumor cells and controlling metastatic growth in the liver. Hepatology 23:1224–1231
Luo DZ, Vermijlen D, Ahisali B, Triantis V, Plakoutsi G, Braet F, Vanderkerken K, Wisse E (2000) On the biology of pit cells, the liver-specific NK cells. World J Gastroenterol 6:1–11
Wellner UF, Keck T, Brabletz T (2010) Liver metastases: pathogenesis and oncogenesis. Chirurg 81:551–556
Chiang AC, Massague J (2008) Molecular basis of metastasis. N Engl J Med 359:2814–2823
Paschos KA, Majeed AW, Bird NC (2014) Natural history of hepatic metastases from colorectal-pathological pathways with clinical significance. World J Gastroenterol 20:3719–3737
Giavazzi R, Jessup JM, Campbell DE, Walker SM, Fidler IJ (1986) Experimental nude mouse model of human colorectal cancer liver metastases. J Natl Cancer Inst 77:1303–1308
Morikawa K, Walker SM, Jessup JM, Fidler IJ (1988) In vivo selection of highly metastatic cells from surgical specimens of different human primary colon carcinomas in nude mice. Cancer Res 48:1943–1948
Fidler IJ (1991) Orthotopic implantation of human colon carcinomas into nude mice provides a valuable model for the biology and therapy of metastasis. Cancer Metastasis Rev 10:229–243
Morikawa K, Walker SM, Nakajima M, Pathak S, Jessup JM, Fidler IJ (1988) Influence of organ environment on the growth, selection and metastasis of human colon carcinoma cells in nude mice. Cancer Res 48:6863–6871
Fidler IJ, Wilmanns C, Staroselsky A, Radinsky R, Dong Z, Fan D (1994) Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Metastasis Rev 13:209–243
Radinski R, Risin S, Fan D, Dong Z, Bielenberg D, Bucana CD, Fidler IJ (1995) Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells. Clin Cancer Res 1:19–31
Kitadai Y, Bucana CD, Ellis LM, Anzai H, Tahara E, Fidler IJ (1995) In situ mRNA hybridization technique for analysis of metastasis-related genes in human colon carcinoma cells. Am J Pathol 147:1238–1247
Takahashi Y, Llis LM, Wilson MR, Bucana CD, Kitadai Y (1996) Progressive upregulation of metastasis-related genes in human colon cancer cells implanted into the cecum of nude mice. Oncol Res 8:163–169
Kitadai Y, Sasaki T, Kuwai T, Nakamura T, Bucana CD, Fidler IJ (2006) Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and metastasis of human colon carcinoma. Am J Pathol 169:2054–2065
Kuwai T, Nakamura T, Sasaki T, Kitadai Y, Kim JS, Langley RR, Fan D, Wang X, Do KA, Kim SJ, Fidler IJ (2008) Targeting EGFR, VEGFR, and PDGFR on colon cancer cells is required for therapy. Clin Exp Metastasis 25:477–489
Mao W, Irby R, Coppola D, Fu L, Wloch M, Turner J, Yu H, Garcia R, Jove R, Yeatman TJ (1997) Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential. Oncogene 15:3083–3090
Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, Karl R, Fujita DJ, Jove R, Yeatman TH (1999) Activating SRC mutation in a subset of advanced human colon cancers. Nat Genet 21:187–190
Brinckerhoff CE, Matrisian LM (2002) Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 390:91–97
Overall CM, Lopez-Otin C (2007) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2:657–672
Krüger A (2009) Functional genetic mouse models: promising tools for investigation of the proteolytic internet. Biol Chem 390:91–97
Krüger A, Kates RE, Edwards DR (2009) Avoiding spam in the proteolytic internet: future strategies for anti-metastatic MMP inhibition. Biochim Biophys Acta 1803:95–102
Han J, Gao B, Jin X, Li Z, Sun Y, Song B (2012) Small interfering RNA down-regulation of β-catenin inhibits invasion of colon cancer cells in vitro. Med Sci Monit 18:BR273–BR280
Damodharan U, Ganesan R, Radhakrishnan UC (2011) Expression of MMP2 and MMP9 gelatinases in human colon cancer cells. Appl Biochem Biotechnol 165:1245–1252
Krüger A, Soeltl R, Sopov I, Kopitz C, Artl M, Magdolen V, Harbeck N, Gänsbacher B, Schmitt M (2001) Hydroxamate-type matrix metalloprotease inhibitor batimastat promotes liver metastasis. Cancer Res 61:1272–1275
Clinchi B, Fransson A, Druvefors B, Hellsten A, Hakansson A, Gustavson B, Sjödahl R, Hakanson L (2007) Preoperative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma. Cancer 109:1742–1749
Gerg M, Kopitz C, Schaten S et al (2008) Distinct functionality of tumor cell-derived gelatinases during formation of liver metastases. Mol Cancer Res 6:341–351
Arlt M, Kopitz C, Pennington C et al (2002) Increase in gelatinase-specificity of matrix metalloprotease inhibitors correlates with antimetastatic efficacy in a T-cell lymphoma model. Cancer Res 62:5543–5550
Seubert B, Grünwald B, Kobuch J et al (2014) TIMP1 creates a pre-metastatic niche in the liver through SDF/CXCR4-dependent neutrophil recruitment in mice. Hepatology 61:238–248
Moller Sorensen N, Veigaard Sorensen I, Ornbierg Würtz S et al (2008) Biology and potential clinical implications of tissue inhibitor of metalloproteinases-1 in colorectal cancer treatment. Scand J Gastroenterol 43:774–786
Holten-Andersen MN, Stephens RW, Nielsen HJ et al (2000) High preoperative plasma tissue inhibitor of metalloproteinases-1 levels are associated with short survival of patients with colorectal cancer. Clin Cancer Res 6:4292–4299
Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9:285–293
Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21:139–146
Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G (2012) Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12:89–103
Liu Y, Yu X-F, Zou J, Luo Z-H (2015) Prognostic value of c-MET in colorectal cancer: a meta-analysis. World J Gastroenterol 21:3706–3710
Liu Y, Li Q, Zhu L (2012) Expression of hepatocyte growth factor and c-MET in colon cancer: correlation with clinicopathological features and overall survival. Tumori 98:105–112
Luraghi P, Schelter F, Krüger A, Boccaccio C (2012) The MET oncogene as a therapeutic target in cancer invasive growth. Front Pharmacol 3:164
Kopitz C, Gerg M, Bandapalli OR et al (2007) Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling. Cancer Res 67:8615–8623
Murphy G (2011) Tissue inhibitors of metalloproteases. Genome Biol 12:233
Schelter F, Grandl M, Seubert B et al (2011) Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met signaling via inhibition of Adam-10. Clin Exp Metastasis 28:793–802
Schrötzlmair F, Kopitz C, Halbgewachs B (2010) Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by host-derived urokinase type plasminogen activator. J Cell Mol Med 14:2760–2770
Schelter F, Halbgewachs B, Bäumler P et al (2010) Tissue inhibitor of metalloproteinases-1 induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α. Clin Exp Metastasis 28:91–99
Schelter F, Gerg M, Halbgewachs B et al (2010) Identification of survival-independent metastasis enhancing role of hypoxia-inducible factor-1 alpha with a hypoxia-tolerant tumor cell line. J Biol Chem 285:26182–26189
Jung KK, Liu XW, Chirco R, Fridman R, Kim HR (2006) Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J 25:3934–3942
Toricelli M, Melo FH, Peres GB, Siulva DC, Jasiulionis MG (2013) Timp1 interacts with beta-1 integrin and CD63 along melanoma genesis and confers anoikis resistance by activating PI3 K signaling pathway independently of Akt phosphorylation. Mol Cancer 12:51
Puissegur MP, Mazure NM, Bertero P et al (2011) miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ 18:465–478
Cui A, Seubert B, Stahl E et al (2014) Tissue inhibitor of metalloproteinases-1 induces a protumorigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes. Oncogene in press
Cui H, Grosso S, Schelter F, Mari B, Krueger A (2012) On the prometastatic stress response in cancer therapies: evidence for a positive cooperation between TIMP-1, HIF-1α and miR-210. Front Pharmacol 3:134
Mason SD, Joyce JA (2011) Proteolytic networks in cancer. Trends Cell Biol 21:228–237
Sorensen NM, Byström P, Christensen IJ et al (2007) TIMP-1 is significantly associated with objective response and survival in metastatic colorectal cancer patients receiving a combination of irinotecan, 5-fluoruracil, and folinic acid. Clin Cancer Res 13:4117–4122
Stein U, Walther W, Arlt F et al (2009) MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med 15:59–67
Isella C, Mellano A, Galimi F et al (2013) MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases. Ann Surg 257:1089–1095
Stein U, Burock S, Herrmann P et al (2012) Circulating MACC1 transcripts in colorectal cancer patient plasma predict metastasis and prognosis. PLoS ONE 7:e49249
Stein U, Dahlmann M, Walther W (2010) MACC1 – more then metastasis? Facts and predictions about a novel gene. J Mol Med 88:11–18
Arlt F, Stein U (2009) Colon cancer metastasis: MACC1 and Met as metastatic pacemakers. Int J Biochem Cell Biol 41:2356–2359
Zhang Y, Wang Z, Chen M et al (2012) MicroRNA-143 targets MACC1 to inhibit cell invasion and migration in colorectal cancer. Mol Cancer 11:23
Ostman A, Hellberg C, Böhmer FD (2006) Protein-tyrosine phosphatases and cancer. Nat Rev Cancer 6:307–320
Bessette DC, Qui D, Pallen C (2008) PRL PTPs: mediators and markers of cancer prognosis. Cancer Metastasis Rev 27:231–252
Lee SK, Han YM, Yun J et al (2012) Phosphatase of regenerating liver-3 promotes migration and invasion by upregulating matrix metalloproteinases-7 in human colorectal cancer cells. Int J Cancer 131:E190–E203
Al-Aidaroos AQ, Yuen HD, Guo K (2013) Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells. J Clin Invest 123:3459–3471
Al-Aidaroos AQ, Zeng Q (2010) PRL3 phosphatase and cancer metastasis. J Cell Biochem 111:1087–1098
Saha S, Bardelli A, Buckhaults P et al (2001) A phosphatase associated with metastasis of colorectal cancer. Science 294:1343–1346
Bardelli A, Saha S, Sager JA et al (2003) PRL-3 expression in metastatic cancers. Clin Cancer Res 9:5607–5615
Zeng Q, Dong JM, Guo K et al (2003) PRL-3 and PRL-1 promote cell migration, invasion and metastasis. Cancer Res 63:2716–2722
Jiang Y, Liu XQ, Rajput A et al (2011) Phosphatase PRL-3 is a direct regulatory target of TGFβ in colon cancer metastasis. Cancer Res 71:234–244
Guo K, Tang JP, Tan CP, Wang H, Zeng Q (2008) Monoclonal antibodies target intracellular PRL phosphatases to inhibit cancer metastases in mice. Cancer Biol Ther 7:750–757
Guo K, Tang JP, Al-Aidaroos AQ et al (2012) Engineering the first chimeric antibody in targeting intracellular PRL-3 oncoprotein for cancer therapy in mice. Oncotarget 3:158–171
Weidle UH, Eggle D, Klostermann S (2009) L1-CAM as a target for treatment of cancer with monoclonal antibodies. Anticancer Res 29:4919–4931
Gavert S, Conacci-Sorell M, Gast D et al (2005) L1, a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive front of colon tumors. J Cell Biol 168:633–642
Gerg M, Kopitz C, Schaten S et al (2008) Distinct functionality of tumor-cell derived gelatinases during formation of liver metastases. Mol Cancer Res 6:341–351
Weinspach D, Seubert B, Schaten S et al (2014) Role of L1 cell adhesion molecule (L1CAM) in the metastatic cascade: promotion of dissemination, colonization and metastatic growth. Clin Exp Metastasis 31:87–100
Lim IT, Brown S, Mobashery S (2004) A convenient synthesis of a selective gelatinase inhibitor as an antimetastatic agent. J Org Chem 69:3572–3573
Coutelle O, Nyakatura G, Tsudien S et al (1998) The neural cell adhesion molecule L1: genomic organisation and differential splicing is conserved between man and the pufferfish fugu. Gene 208:7–15
De Angelis E, Brummendorf T, Cheng L, Lemmon V, Kenwrick S (2001) Alternative use of a mini exon of the L1 gene affects L1 binding to neural ligands. J Biol Chem 276:32738–32742
Kamiguchi H, Long KE, Pendergast M, Schaefer AW, Rapoport I, Kirchhausen T, Lemmon V (1998) The neural cell adhesion molecule L1 interacts with the AP-2 adaptor and is endocytosed via its clathrin-mediated pathway. J Neurosc 18:5311–5321
Hauser S, Bickel L, Weinspach D et al (2011) Full-length L1CAM and not its ∆2∆27 splice variant promotes metastasis through induction of gelatinase expression. PLoS One 6:e18989
Gast D, Riedle S, Kiefel H et al (2008) The RGD integrin binding site in human L1-CAM is important for nuclear signaling. Exp Cell Res 314:2411–2418
Gavert N, Ben-Shmuel A, Lemmon V, Brabletz T, Ben-Zeév A (2010) Nuclear factor-kappa B signaling and ezrin are essential for L1-mediated metastasis of colon cancer cells. J Cell Sci 123:2135–2143
Gast D, Riedle S, Issa Y et al (2008) The cytoplasmic part of L1-CAM controls growth and gene expression in human tumors that is reversed by therapeutic antibodies. Oncogene 27:1281–1289
Arlt M, Novak-Hofer I, Gast D et al (2006) Efficient inhibition of intra-peritoneal tumor growth and dissemination of human ovarian carcinoma cells in nude mice by anti-L1-cell adhesion molecule monoclonal antibody treatment. Cancer Res 66:936–943
Wolterink S, Moldenhauer G, Fogel M et al (2010) Therapeutic antibodies to human L1CAM: functional characterization and application in a mouse model for ovarian carcinoma. Cancer Res 70:2504–2515
Schäfer H, Dieckmann C, Kornijenko O et al (2012) Combined treatment of L1CAM antibodies and cytotstatic drugs improve the therapeutic response to pancreatic and ovarian carcinoma. Cancer Lett 319:66–82
Kaifi JT, Reichelt U, Quaas A et al (2007) L1 is associated with micrometastatic spread and poor outcome in colorectal cancer. Mod Pathol 20:1183–1190
Boo YJ, Park JM, Kim J et al (2007) L1 expression as a marker for poor diagnosis, tumor progression, and short survival in patients with colorectal cancer. Ann Surg Oncol 14:1703–1711
Gavert N, Sheffer M, Raveh S et al (2007) Expression of L1-CAM and ADAM 10 in human colon cancer cells induces metastasis. Cancer Res 67:7703–7712
Gavert N, Conacci-Sorrell M, Gast D et al (2005) L1, a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. J Cell Biol 168:633–642
Gavert N, Ben-Shmuel A, Raveh S, Ben-Zeév A (2008) L1-CAM in cancerous tissues. Expert Opin Biol Ther 8:1749–1757
Trerotola M, Cantanelli P, Guerra E et al (2013) Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene 32:222–233
Wang J, Day R, Dong Y, Weintraub SJ, Michel L (2008) Identification of Trop-2 as an oncogene and an attractive target in colon cancers. Mol Cancer Ther 7:280–285
Cubas R, Zhang S, Li M, Chen C, Yao Q (2010) Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. Mol Cancer 9:253
Guerra E, Trerotola M, Aloisi AL et al (2013) The Trop-2 signaling network in cancer growth. Oncogene 32:1594–1600
Ohmachi T, Taneka Miori K, Inoue H, Yanaga K, Mori M (2006) Clinical significance of TROP2 expression in colorectal cancer. Clin Cancer Res 12:3057–3063
Fang YH, Lu ZH, Wang GQ et al (2007) Elevated expression of MMP7, TROP2, and Survivin are associated with survival, disease recurrence, and liver metastasis of colon cancer. Int J Colorectal Dis 24:875–884
Alberti S, Trerotola G, Vaca R et al (2007) TROP2 is a major determinant of growth and metastatic spreading of human cancer. J Clin Oncol 25(18S):10510
Donato R, Cannon BR, Sorci G et al (2013) Functions of S100 proteins. Curr Mol Med 1:24–57
Sack U, Walther W, Scuderio D et al (2011) S100A4-induced cell motility and metastasis is restricted by the Wnt/β-catenin pathway inhibitor calcimycin in colon cancer cells. Mol Biol Cell 22:3344–3354
Cho YG, Kim CJ, Nam SW (2005) Overexpression of S100A4 is closely associated with progression of colorectal cancer. World J Gastroenterol 11:4852–4856
Boye K, Nesland JM, Sandstad B, Maelandsmo GM, Flatmark K (2007) Nuclear S100A4 is a novel prognostic marker in colorectal cancer. Eur J Cancer 46:2919–2925
Dahlmann M, Sack U, Herrmann P et al (2012) Systemic shRNA mediated knock down of S100A4 in colorectal cancer xenografted mice reduces metastasis formation. Oncotarget 3:783–797
Stein U, Arlt F, Walther W et al (2006) The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer. Gastroenterology 131:1486–1500
Ding Q, Chang CJ, Xie X et al (2011) APOBEC3G promotes liver metastasis in an orthotopic mouse model of colorectal cancer and predicts human hepatic metastasis. J Clin Invest 121:4526–4536
Wang Q, Zhang YN, Lin GL et al (2012) S100P, a potential novel prognostic marker in colorectal cancer. Oncol Rep 28:303–310
Chandramouli A, Mercado-Pimentel ME, Hutchinson A et al (2010) The induction of S100P expression by the prostaglandin E2 (PGE2/EP4 receptor signaling pathway in colon cancer cells. Cancer Biol Ther 28:303–310
Dong L, Wang F, Yin X et al (2014) Overexpression of S100P promotes colorectal cancer metastasis and decreases chemosensitivity to 5-FU in vitro. Mol Cell Biochem 389:257–264
Wong H, Schotz MC (2002) The lipase gene family. J Lipid Res 43:993–999
Nomura DK, Long JZ, Niessen S et al (2010) Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140:49–61
Notarnicola M, Messa C, Caruso MG (2012) A significant role of lipogenic enzymes in colorectal cancer. Anticancer Res 32:2585–2590
Silinsky J, Grimes C, Driscoll T et al (2013) CD 133+ and CXCR4+ colon cancer cells as a marker for lymph node metastasis. J Surg Res 185:113–118
Shmelkov SV, Butler JM, Hooper AT et al (2008) CD133 expression is not restricted to stem cells, and both CD133+ and CD133− colon cancer cells initiate tumors. J Clin Invest 118:2111–2120
Jaszczur M, Bertram JG, Pham P, Scharff MD, Goodman MF (2013) AID and Apobec3G haphazard deamination and mutational diversity. Cell Mol Life Sci 70:3089–3108
Huang J, Liang Z, Yang B, Tian H, Ma J, Zhang H (2007) Derepression of microRNA-mediated protein translation inhibition by apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) and its family members. J Biol Chem 282:33632–33640
Gallois-Montbrun S, Kramer B, Swanson CM et al (2007) Antiviral protein APOBEC3G localizes to ribonucleoprotein complexes found in P bodies and stress granules. J Virol 81:2165–2178
Ranganathan P, Weaver KL, Capobianco AJ (2011) Notch signalling in solid tumors: a little bit of everything but not all the time. Nat Rev Cancer 11:338–351
Sonoshita M, Aoki M, Fuwa H et al (2011) Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell 19:125–137
Katz LH, Li Y, Chen J-S et al (2013) Targeting TGFβ signaling in cancer. Exp Opin Ther Targets 17:743–760
Pickup M, Novitsky S, Moses HL (2013) The role of TGFβ in the tumor microenvironment. Nat Rev Cancer 13:788–799
Zhang B, Halder SK, Kashikar ND et al (2010) Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology 138:969–980
Halder SK, Rachakonda G, Deane NG, Datta PK (2008) Smad7 induces hepatic metastasis in colorectal cancer. Br J Cancer 99:957–965
Calon A, Espinet E, Palomo-Ponce S et al (2012) Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 22:571–584
Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361:2449–2460
Shibayama M, Maak M, Nitsche U et al (2011) Prediction of metastasis and recurrence in colorectal cancer based on gene expression analysis: ready for the clinic? Cancers 3:2858–2869
Taketo MM (2011) Reflections on the spread of metastasis to cancer prevention. Cancer Prev Res 4:324–328
Ye L-C, Liu T-S, Ren L et al (2013) Randomized controlled clinical trial of cetuximab plus chemotherapy for patients with KRAS unresectable colorectal liver-limited metastasis. J Clin Oncol 31:1931–1938
Acknowledgments
This work was supported by Grants to A.K. from Deutsche Forschungsgemeinschaft (KR2047 1-2, KR2047 1-3, KR2047 3-1, and KR2047 4-2) and the European Union Research Framework Programme 7 (HEALTH-2007-201279/Microenvimet, and NMP-2010-263307/SaveMe).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Weidle, U.H., Birzele, F. & Krüger, A. Molecular targets and pathways involved in liver metastasis of colorectal cancer. Clin Exp Metastasis 32, 623–635 (2015). https://doi.org/10.1007/s10585-015-9732-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10585-015-9732-3