Dan Huang, Xiang Du, Department of Pathology, Cancer Hospital of Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Author contributions: Du X designed the research and Huang D wrote the paper.
Supported by The Science and Technology Development Foundation of Shanghai, No. 064119512
Correspondence to: Xiang Du, 270 Dong An Road, Department of Pathology, Cancer Hospital, Fudan University, Shanghai 200032, China. firstname.lastname@example.org
Telephone: +86-21-64175590-3357 Fax: +86-21-64174774
Received: November 3, 2007 Revised: January 30, 2008
Invasion and metastasis are the deadly face of malignant tumors. Considering the high rate of incidence and mortality of colorectal cancer, it is critical to determine the mechanisms of its dissemination. In the parallel investigation of the invasive front and tumor center area of colorectal cancer (CRC), observation of heterogeneous b-catenin distribution and epithelial-mesenchymal transition (EMT) at the invasive front suggested that there might be a crosstalk between tumor cells and the tumor microenvironment. Wnt signaling pathway is also involved in the cancer progression due to its key role in CRC tumorigenesis. Moreover, in recent years, there is increasing evidence that the regulators of microenvironment, including extracellular matrix, growth factors and inflammatory factors, are associated with the activation of Wnt pathway and the mobility of tumor cells. In this review, we will try to explain how these molecules trigger metastasis via the Wnt pathway.
© 2008 WJG. All rights reserved.
Key words: Invasion; Microenvironment; Colorectal cancer; Epithelial-mesenchymal transition; Wnt; b-catenin
Peer reviewer: Yasushi Adachi, Dr, First Department of Internal Medicine, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan
Huang D, Du X. Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination. World J Gastroenterol 2008; 14(12): 1823-1827 Available from: URL: http://www.wjgnet.com/1007-9327/14/1823.asp DOI: http://dx.doi.org/10.3748/wjg.14.1823
Colorectal cancer (CRC) is one of the major malignancies worldwide and the second leading cause of cancer death in the United States. In the past decades, many researches in tumorigenesis and progression of CRC have focused on genes and epigenetic changes. Recently, increasing attention has been paid to cellular signal transduction in CRC, especially Wnt pathway which regulates cell growth, differentiation and death in embryogenesis and tumor development, attributing to the presence of an activating mutation of the canonical Wnt signaling pathway in about 90% of all CRCs[2-6]. Activation of the Wnt signaling pathway is characterized by the accumulation of b-catenin in nuclei. It was reported that nuclear b-catenin is detectable in colorectal tumors and its amount is increased from early adenomas to adenocarcinomas . However, the distribution of b-catenin within an individual tumor is very heterogeneous. Immunohistochemical analysis of moderately- and well-differentiated colon adenocarcinomas reveals that accumulation of nuclear b-catenin is observed in dedifferentiated tumor cells at the invasive front and scattered in the adjacent stromal compartment. Contrarily, in central differentiated area, it is detectable on the membrane and its translocation is not found[9,10]. Consequently, there is considerable interest in finding the means to explain such dynamic changes. Recent researches highlight the role of tumor microenvironment in cancer dissemination where cells located at the invasive front are exposed to cytokines, such as growth factors, chemokines, inflammatory factors, and extracellular matrix, which may interact with the Wnt signaling pathway resulting in the heterogeneous intracellular distribution of b-catenin[11-13]. Therefore, this review will concentrate on the relationship between microenvironment and Wnt pathway in invasion and metastasis of CRC.
WNT PATHWAY IN CRC
The Wnt signaling pathway is involved in various differentiation events both in embryogenesis and in tumor formation when aberrantly activated. Molecular studies demonstrated that constitutive activation of Wnt/b-catenin signaling occurs in nearly all colorectal tumors due to mutations either in APC gene or in less frequently b-catenin[14,15]. Therefore, understanding the role of this pathway in CRC carcinogenesis is important.
In the absence of Wnt signaling, intracellular b-catenin levels are regulated by multiprotein complex encompassing the adenomatous polyposis coli (APC) protein, axin, and glycogen synthase kinase 3b (GSK3b). The complex phosphorylates b-catenin making it for subsequent ubiquitination and degradation (Figure 1A). In the stimulated cells, Wnt ligands bind to one of the Wnt receptors, co-activating low-density lipoprotein receptor-related proteins (LRP). Binding of Wnts leads to phosphorylation of the cytoplasmic protein Dishevlled (Dsh) and consequently Dsh binds to axin resulting in dissociation of the complex and stabilization of b-catenin (Figure 1B). Intracellular b-catenin accumulation results in its nuclear translocation, nevertheless the molecular mechanism is still unclear. In nuclei, b-catenin works as a cofactor for transcription factors of the T-cell factor/lymphoid enhancing factor (TCF/LEF), modulating the expression of a broad spectrum of target genes (Table 1), which affects stemness, proliferation and differentiation.
In 85% familial and sporadic CRCs, the APC gene mutations lead to loss of b-catenin degradation of the complex function and intracellular b-catenin accumulation and translocation, which is the mark of active Wnt signaling. Accordingly, constitutive activation of this Wnt-b-catenin-TCF pathway, also called canonical Wnt pathway, is blamed for carcinogenesis in CRC.
The non-canonical Wnt pathway independent of b-catenin includes the planar-cell-polarity (PCP)-like pathway that guides cell movements during gastrulation and the Wnt/Ca2+ pathway. Up to now, how these pathways are involved in tumorigenesis or cancer progression is still unknown. However, there is evidence that Wnts acting through the non-canonical pathway can promote tumor progression[16-19]. Experiments have been carried out by co-culture of breast tumor cells with macrophages, revealing that a canonical pathway in tumor cells is a necessary prerequisite. However, non-canonical pathway via Wnt5a is critical for macrophage-induced invasiveness.
b-CATENIN IN CRC PROGRESSION
The capability of invasion and metastasis is the hallmark of malignant tumors. The progression of tumor cellular dissemination leading to invasive growth includes the detachment from primary cancer, migration, access to blood or lymphatic vessels and development of secondary tumors. Cellular dissemination is characterized by disordered cell-cell interactions and cell adhesion. Disintegration of cell adhesion molecules, especially b-catenin, has been implicated in this process. However, only b-catenin in the membranes, a stable subcellular localization, forms an adherent complex with a-catenin and E-cadherin which is regulated by tyrosine phosphorylation. Phosphorylated b-catenin is dissociated from the adherent complex and transferred to the cytoplasm, where b-catenin can be degraded or translocated into nuclei, triggering dysregulation of Wnt pathway. Importantly, cooperative effects on tumor development of defects in E-cadherin-mediated cell adhesion and activation of b-catenin-medicated signal transduction are observed in human CRC. Moreover, a tissue microarray-based analysis of a large number of cases, performed by Lugli et al demonstrated that increased nuclear b-catenin expression and loss of membranous E-cadherin are two independent, adverse prognostic factors in sporadic CRC, suggesting that the role of b-catenin in tumor invasion and metastasis is not just attributed to interaction with E-cadherin, therefore other mechanisms may be involved, such as Wnt/b-catenin signaling pathway.
Furthermore, as the downstream effector of canonical Wnt pathway, nuclear b-catenin cooperating with TCF/LEF initiates expression of target genes (Table 1), some of which can improve tumor progression. MMP-7, a target of b-catenin/TCF signaling, is expressed in up to 90% of CRCs and its expression in the invasive front as well as in urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) is related to unfavorable outcome in CRC[22,23]. Fascin, a novel target of b-catenin/TCF signaling, is expressed at the invasive front of human colon cancer, suggesting that it plays a potential role in the development of colon cancer metastasis. It was reported that intratumorous heterogeneity in CRC correlates with differential expression of 510 genes between the central tumor region and the invasive front, isolated by laser-microdissection in the same tumor samples. This in vivo analysis shows over-expression of known Wnt/b-catenin target genes either in the entire tumor tissue or specifically at the invasive front. Whether these target genes expressed at the front are involved in the tumor invasive process still needs to be further studied. Furthermore, the concomitant high expression in 2 groups of Wnt/b-catenin target genes, inflammation- and tissue repair-related genes, at the invasive front supports the hypothesis that inflammation-activated microenvironment may trigger selective Wnt/b-catenin target gene expression and contribute to the progression of CRC. Accordingly, similar in tumor initiation, Wnt pathway activation (detectable by nuclear accumulation of b-catenin and expression of some target genes) might be functionally associated with cancer dissemination.
In modestly- and well-differentiated tumor, membranous expression of b-catenin in tumor center retains whereas nuclear b-catenin is observed in dedifferentiated tumor cells localized in the invasive area. Since tumor cells in an individual tumor harbor APC mutations, this alteration alone cannot lead to the heterogeneous distribution of b-catenin, but its translocation has to be explained by additional events. Whether nuclear b-catenin accumulation is the sign of motility enhancement of tumor cells and what initiates b-catenin heterogeneous distribution, are two questions arising from these observations.
EPITHELIAL-MESENCHYMAL TRANSITION IN CRC DEVELOPMENT
In the majority of sporadic CRCs, well-, modestly-, and well-differentiated adenocarcinomas, tumor cells at the invasive front lose their epithelial characteristics and take on the properties that are typical of mesenchymal cells, which require complex changes in cell architecture and behavior. Such transition from epithelial- to mesenchymal- cells, dubbed as epithelial-mesenchymal transition (EMT), is considered a fundamental event in the metastatic cascade. The essential features of it are the disruption of intercellular contacts and the enhancement of cell motility, thereby leading to release of cells from the parent epithelial tissue. The resulting phenotype is suitable for migration and, thus, for tumor invasion and dissemination, allowing metastasis progression to proceed. Although the molecular bases of EMT have not been completely elucidated, several interconnected transduction pathways and a number of potentially involved signaling molecules, including b-catenin, have been identified[27,28].
Activated b-catenin is directly linked to EMT. The activation of Wnt signal pathway results in the activation of b-catenin/TCF transcriptional regulators such as snail[29,30] and slug, which regulate the changes in gene-expression patterns underlying EMT. Similarly, in the study of breast cancer cells, Yook et al demonstrated that canonical Wnt pathway engages tumor cell dedifferentiation and tissue-invasive ability through an axin-2-dependent pathway to identify a new mechanistic b-catenin-TCF-regulated axin2-GSK3b-Snail1 axis, thus gaining insight into cancer-associated EMT program. It was reported that Wnt/b-catenin signaling pathway plays a pivotal role either in gastric cancer formation or in tumor invasion and dissemination. In cell culture experiments, cells with b-catenin activation lose their polarity and disrupt cell-cell contacts and EMT morphologically[34,35]. Moreover, immunohistochemical stains demonstrate alternations of the actin cytoskeleton in these cells, indicating that nuclear b-catenin accumulation is functionally related to EMT in budding tumor cells at the tumor-host interface.
MICROENVIROMENTAL REGULATION IN b-CATENIN TRANSLOCATION AND EMT INDUCTION
The dynamic changes in the above non-random distribution of b-catenin and EMT of tumor cells at the invasive front of CRC, can be at least partially explained by interactions with the tumor environment. A micro-ecosystem exists at the invasive front of tumor where the stromal cells interact with parenchymal cells by producing extracellular matrix and secreting cytokines that directly or indirectly promote cell invasion[14,36]. Moreover, it also appears that inflammatory cells are involved in the formation of tumor metastasis[25,37].
Epithelial-mesenchymal interactions are essential for intestinal development. Thus, more investigations should be focused on mesenchymal factors, particularly the components of extracellular matrix, because they have a potent regulatory effect on tumor cells. Recent studies demonstrated that Wnt ligands are expressed in both mesenchymal and epithelial cells of the colon. It was also reported that local regulation by Wnt signals of diverse cell signaling pathways in fibroblasts could have multifaceted consequences for tissue microenvironments in vivo, including the balance between cell differentiation and proliferation, as well as between cell migration and adhesion. Mesenchymal forkhead transcription factors, Foxf1 and Foxf2, can limit paracrine Wnt signaling and promote extracellular matrix production in gut, and deletion of Foxf1 and Foxf2 is accompanied with increased mesenchymal expression of Wnt5a and b-catenin nuclear accumulation in epithelial cells, indicating that there is a crosstalk between stromal cells and parenchymal cells involving Wnt signaling. There are extensive data to support the relation between extracellular matrix and signal pathway in tumorigenesis. Tsuboi K et al investigated the relationship of galectin-3 expression, a component of extracellular matrix, to the clinicopathological factors, and found that reduced galectin-3 expression is related to invasion and metastasis of CRC. In contrast to b-catenin, the expression of galectin-3 is lower at the invasive front of a tumor. Whether b-catenin regulates galectin-3 expression or other signaling pathways are involved in the process is still controversial.
In addition, cell culture experiments have also revealed a role of cytokines, such as growth factors, in the intracellular b-catenin distribution, as well as in the induction of EMT. One of the related growth factors is the hepatocyte growth factor (HGF), which is found in CRC. It was reported that HGFR and b-catenin physically interact in a complex, which is disassembled after HGF treatment. Moreover, HGF treatment promotes b-catenin/TCF transcriptional activity in CRC cells. HGF also stimulates cells leading to cell scattering. Therefore, a self-amplifying positive feedback loop between HGFR and b-catenin in CRC promotes tumor growth and invasion. Like HGF, Platelet-derived growth factor (PDGF) also can activate EMT in CRC cells by enhancing Wnt signaling. A recent study has shown a novel Wnt-independent pathway that enhances b-catenin signaling to nuclei. PDGF promotes tyrosine phosphorylation of p68, which binds to b-catenin and inhibits its phosphorylation by GSK3b. A new EMT pathway from PDGF and another route to nuclear b-catenin signaling have been identified. Similarly, the epidermal growth factor (EGF) and transforming growth factor b (TGFb) can also enhance Wnt/b-catenin signaling by posphorylating p68.
It has been widely accepted that inflammatory cells in colorectal tumors are associated with the progression to malignancy. Brown et al reported that non-steroidal anti-inflammatory drugs (NSAIDs) can decrease the number and size of intestinal polyps in Apc-mutation mice by inhibiting cyclooxygenase-2 (COX-2), one of the main enzymes in prostaglandin biosynthesis. To investigate the mechanism, a recent study by Castellone and collaborators indicate that COX-2 and its proinflammatory metabolite prostaglandin E2 (PGE2) enhance colon cancer progression via its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2. This signaling route involves the activation of PI3K and protein kinase Ake by free G protein and is directly associated with the G protein signaling (RGS) domain of axin, thus leading to GSK3b inactivation, relief of inhibitory phosphorylation of b-catenin and activation of Wnt signaling pathway. Therefore, these findings suggest that COX-2 and inflammation can promote the progression of colon cancer. It was recently reported that co-culture of tumor cells and macrophages leads to up-regulation of Wnt5a in the latter and that non-canonical signaling via Wnt5a in cancer cells is critical for invasion. However, whether a similar interaction between cancer cells and tumor-associated macrophages occurs in CRC is still unknown.
Since tumor cells at the invasive front display nuclear accumulation of b-catenin and EMT features associated with local activation of Wnt signaling pathway, dissemination of cancer cells is not due to gene mutation alone. The importance of tumor microenvironment where extracellular matrix, growth factors and inflammatory factors play a key role in tumor invasion cannot be overlooked. A complex network, which is orchestrated by Wnt pathway and other signaling pathways, may be involved in the regulation of tumor-microenvironment crosstalk. Further study is needed to investigate the specific role of tumor cells and the microenvironment of tumor in invasiveness. Although recent researches have illuminated the involvement of Wnt pathway in cancer development, a more comprehensive view of how cancer spreads will likely emerge in the future, allowing us to provide new potential therapeutic targets for the treatment of aggressive and recurrent CRC in clinical practice.
1 Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007; 57: 43-66 PubMed
2 Miller JR, Hocking AM, Brown JD, Moon RT. Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene 1999; 18: 7860-7872 PubMed
3 Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14: 1837-1851 PubMed
4 Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 2003; 1653: 1-24 PubMed
5 Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature 2001; 411: 349-354 PubMed
6 Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000; 103: 311-320 PubMed
7 Wong NA, Pignatelli M. Beta-catenin--a linchpin in colorectal carcinogenesis? Am J Pathol 2002; 160: 389-401 PubMed
8 Brabletz T, Herrmann K, Jung A, Faller G, Kirchner T. Expression of nuclear beta-catenin and c-myc is correlated with tumor size but not with proliferative activity of colorectal adenomas. Am J Pathol 2000; 156: 865-870 PubMed
9 Kirchner T, Brabletz T. Patterning and nuclear beta-catenin expression in the colonic adenoma-carcinoma sequence. Analogies with embryonic gastrulation. Am J Pathol 2000; 157: 1113-1121 PubMed
10 Brabletz T, Jung A, Hermann K, Gunther K, Hohenberger W, Kirchner T. Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract 1998; 194: 701-704 PubMed
11 Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 2005; 310: 1504-1510 PubMed
12 Yang L, Lin C, Liu ZR. P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell 2006; 127: 139-155 PubMed
13 Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006; 127: 679-695 PubMed
14 Doucas H, Garcea G, Neal CP, Manson MM, Berry DP. Changes in the Wnt signalling pathway in gastrointestinal cancers and their prognostic significance. Eur J Cancer 2005; 41: 365-379 PubMed
15 Segditsas S, Tomlinson I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 2006; 25: 7531-7537 PubMed
16 Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. J Cell Sci 2003; 116: 2627-2634 PubMed
17 Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, Trent JM. Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 2002; 1: 279-288 PubMed
18 Jonsson M, Dejmek J, Bendahl PO, Andersson T. Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas. Cancer Res 2002; 62: 409-416 PubMed
19 Pukrop T, Klemm F, Hagemann T, Gradl D, Schulz M, Siemes S, Trumper L, Binder C. Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. Proc Natl Acad Sci USA 2006; 103: 5454-5459 PubMed
20 Fuchs SY, Ougolkov AV, Spiegelman VS, Minamoto T. Oncogenic beta-catenin signaling networks in colorectal cancer. Cell Cycle 2005; 4: 1522-1539 PubMed
21 Lugli A, Zlobec I, Minoo P, Baker K, Tornillo L, Terracciano L, Jass JR. Prognostic significance of the wnt signalling pathway molecules APC, beta-catenin and E-cadherin in colorectal cancer: a tissue microarray-based analysis. Histopathology 2007; 50: 453-464 PubMed
22 Adachi Y, Yamamoto H, Itoh F, Arimura Y, Nishi M, Endo T, Imai K. Clinicopathologic and prognostic significance of matrilysin expression at the invasive front in human colorectal cancers. Int J Cancer 2001; 95: 290-294 PubMed
23 Hiendlmeyer E, Regus S, Wassermann S, Hlubek F, Haynl A, Dimmler A, Koch C, Knoll C, van Beest M, Reuning U, Brabletz T, Kirchner T, Jung A. Beta-catenin up-regulates the expression of the urokinase plasminogen activator in human colorectal tumors. Cancer Res 2004; 64: 1209-1214 PubMed
24 Vignjevic D, Schoumacher M, Gavert N, Janssen KP, Jih G, Lae M, Louvard D, Ben-Ze'ev A, Robine S. Fascin, a novel target of beta-catenin-TCF signaling, is expressed at the invasive front of human colon cancer. Cancer Res 2007; 67: 6844-6853 PubMed
25 Hlubek F, Brabletz T, Budczies J, Pfeiffer S, Jung A, Kirchner T. Heterogeneous expression of Wnt/beta-catenin target genes within colorectal cancer. Int J Cancer 2007; 121: 1941-1948 PubMed
26 Prall F, Weirich V, Ostwald C. Phenotypes of invasion in sporadic colorectal carcinomas related to aberrations of the adenomatous polyposis coli (APC) gene. Histopathology 2007; 50: 318-330 PubMed
27 Jass JR, Barker M, Fraser L, Walsh MD, Whitehall VL, Gabrielli B, Young J, Leggett BA. APC mutation and tumour budding in colorectal cancer. J Clin Pathol 2003; 56: 69-73 PubMed
28 Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006; 7: 131-142 PubMed
29 Olmeda D, Jorda M, Peinado H, Fabra A, Cano A. Snail silencing effectively suppresses tumour growth and invasiveness. Oncogene 2007; 26: 1862-1874 PubMed
30 Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004; 6: 931-940 PubMed
31 Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 2005; 132: 3151-3161 PubMed
32 Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, Cha SY, Ryu JK, Choi YJ, Kim J, Fearon ER, Weiss SJ. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol 2006; 8: 1398-1406 PubMed
33 Cheng XX, Wang ZC, Chen XY, Sun Y, Kong QY, Liu J, Li H. Correlation of Wnt-2 expression and beta-catenin intracellular accumulation in Chinese gastric cancers: relevance with tumour dissemination. Cancer Lett 2005; 223: 339-347 PubMed
34 Mariadason JM, Bordonaro M, Aslam F, Shi L, Kuraguchi M, Velcich A, Augenlicht LH. Down-regulation of beta-catenin TCF signaling is linked to colonic epithelial cell differentiation. Cancer Res 2001; 61: 3465-3471 PubMed
35 Naishiro Y, Yamada T, Takaoka AS, Hayashi R, Hasegawa F, Imai K, Hirohashi S. Restoration of epithelial cell polarity in a colorectal cancer cell line by suppression of beta-catenin/T-cell factor 4-mediated gene transactivation. Cancer Res 2001; 61: 2751-2758 PubMed
36 Klapholz-Brown Z, Walmsley GG, Nusse YM, Nusse R, Brown PO. Transcriptional program induced by wnt protein in human fibroblasts suggests mechanisms for cell cooperativity in defining tissue microenvironments. PLoS ONE 2007; 2: e945 PubMed
37 Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 2005; 310: 1504-1510 PubMed
38 Gregorieff A, Pinto D, Begthel H, Destree O, Kielman M, Clevers H. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 2005; 129: 626-638 PubMed
39 Ormestad M, Astorga J, Landgren H, Wang T, Johansson BR, Miura N, Carlsson P. Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production. Development 2006; 133: 833-843 PubMed
40 Tsuboi K, Shimura T, Masuda N, Ide M, Tsutsumi S, Yamaguchi S, Asao T, Kuwano H. Galectin-3 expression in colorectal cancer: relation to invasion and metastasis. Anticancer Res 2007; 27: 2289-2296 PubMed
41 Mimeault M, Batra SK. Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies. Ann Oncol 2007; 18: 1605-1619 PubMed
42 Rasola A, Fassetta M, De Bacco F, D'Alessandro L, Gramaglia D, Di Renzo MF, Comoglio PM. A positive feedback loop between hepatocyte growth factor receptor and beta-catenin sustains colorectal cancer cell invasive growth. Oncogene 2007; 26: 1078-1087 PubMed
43 He X. Unwinding a path to nuclear beta-catenin. Cell 2006; 127: 40-42 PubMed
44 Brown JR, DuBois RN. COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol 2005; 23: 2840-2855 PubMed
S- Editor Li DL L- Editor Wang XL E- Editor Liu Y