"Development and Cancer: At the Crossroads of Nodal and Notch Signaling".

Luigi Strizzi ¹, Katharine M. Hardy ¹, Elisabeth A. Seftor ¹, Fabricio F. Costa ¹, Dawn A. Kirschmann ¹, Richard E.B. Seftor ¹, Lynne-Marie Postovit ², and Mary J.C. Hendrix ¹

¹ Children's Memorial Research Center, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois
² The Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada

Requests for reprints: Mary J.C. Hendrix, Northwestern University Feinberg School of Medicine, 2300 Children's Plaza, Box 222, Chicago, IL 60614. Phone: 773-755-6528; Fax: 773-755-6534;
E-mail: MJChendrix@childrensmemorial.org

Aggressive tumor cells express a plastic, multipotent phenotype similar to embryonic stem cells. However, the absence of major regulatory checkpoints in these tumor cells allows aberrant activation of embryonic signaling pathways, which seems to contribute to their plastic phenotype. Emerging evidence showing the molecular cross-talk between two major stem cell signaling pathways Nodal and Notch suggests a promising therapeutic strategy that could target aggressive tumor cells on the basis of their unique plasticity, and provide new insights into the mechanisms underlying the re-emergence of developmental signaling pathways during tumor progression.

It is becoming increasingly clear that regulators of cell fate during embryonic development may also play a role during tumorigenesis. Notch and Nodal are two examples of such regulators. Nodal, a member of the transforming growth factor (TGF)-beta family of proteins, is involved in stem cell maintenance and differentiation, and shown to be associated with cancer progression (1, 2). Notch is an evolutionary highly conserved transmembrane receptor involved in cellular proliferation and differentiation, which is often exploited by cancer cells to promote tumorigenesis and metastasis (3). This review will summarize the role of Notch and Nodal during normal development and cancer, and speculate about the molecular cross-talk between these two signaling pathways in cancer resulting in possible targets for novel therapy.

Nodal and Notch Signaling

Typically, Nodal signals by binding to its co-receptor Cripto-1 and with type I (ALK4/7) and type II (ActRIIB) activin-like kinase receptors (Fig. 1A ; ref. 1). This results in activation of the smad-2/3/4 complex, which translocates to the nucleus where it regulates gene expression by associating with transcription factors including FoxH1 and Mixer (Fig. 1A). Nodal can induce its own transcription as well as the transcription of its inhibitor Lefty (4). The Lefty isoforms, A and B, like Nodal, are TGF-beta family members, and specifically antagonize Nodal signaling by directly binding to Nodal and/or to Cripto-1, thus preventing activation of the ALK receptor complex (Fig. 1A).

Figure 1. Convergence of Nodal and Notch signaling.

Figure 1. Convergence of Nodal and Notch signaling.

A, Nodal can bind to ALK4/7 and ActRIIB receptors and induce smad-2/3/4-dependent signaling in a Cripto-1 dependent or independent manner, leading to activation of target genes including FoxH1, Nodal, and Lefty. Binding of Notch receptors to ligands expressed on adjacent cells leads to enzymatic cleavage by gamma-secretase (g-SC) and intracytoplasmic release of the active NICD. The CSL DNA binding protein can function as a transcriptional repressor. However, when NCID binds to CSL, it forms an activator complex leading to target gene transcription. Cripto-1 may also play a role in regulating Notch expression in melanoma cells (broken arrows).

B, during the establishment of left-right asymmetry in mouse, Nodal expression around the node (ND) is directly regulated by Notch/Delta-like-1 (DLL1) signaling. This domain of Nodal expression is required for the subsequent expression of Nodal in the left lateral plate mesoderm (LLPM), which autoregulates its own expression, as well as the expression of Lefty2 in the LLPM and Lefty1 in the left presumptive floor plate. Together these proteins function to restrict Nodal signaling to the left side of the embryo where it induces left-sided structures. The Nodal coreceptor, CFC1 (Cryptic), an ortholog of human Cripto-1, is symmetrically expressed in both the left and right lateral plate mesoderm (RLPM), as well as in the node and along the left midline. Thin arrows indicate regulation at the transcriptional level. Block symbols indicate regulation at the protein level. Abbreviations: ND, node; NT, notochord, PS, primitive streak; LLPM, left lateral plate mesoderm; RLPM, right lateral plate mesoderm.

C, human embryonic stem cell-conditioned matrix (hESCMTX) contains factors, such as Lefty, capable of repressing Nodal expression in aggressive human melanoma cells (C8161). These cells also show increased miR-302a levels that could inhibit Notch signaling and Nodal expression. Inhibition of Nodal signaling may lead to redifferentiation or apoptosis in C8161 cells.

Canonical Notch signaling is activated upon binding of Notch receptors (Notch 1–4) with their ligands (Delta-like1, 3, and 4, and Jagged1 and 2) expressed on adjacent cells (Fig. 1A; ref. 3). The binding of Notch with its ligands triggers a series of proteolytic cleavages resulting in the release of the Notch intracellular domain (NICD) capable of binding to the CSL (CBF1/RBPjk in vertebrates, Suppressor of Hairless in Drosophila, Lag-1 in Caenorhabditis elegans) DNA binding protein (3). In the absence of NICD, CSL inhibits transcription by associating with co-repressor proteins. NICD activates transcription by competing with these repressor proteins and facilitating the binding of activator complexes to CSL (Fig. 1A). This activating complex is then capable of transcribing target genes including Hes and Hey, and genes implicated in cancer development, such as c-myc, cyclin D1, and p21/Waf1 (3).

Evidence from developmental studies has shown that Notch signaling regulates Nodal expression during the establishment of vertebrate left-right asymmetry (5). In fact, Nodal has been identified as a direct target of Notch activity, and, through promoter analysis, common putative CSL binding sites required for specific Nodal expression around the node have been described (and subsequently in the left lateral plate mesoderm; Fig. 1B).

Nodal and Notch in Cancer

Nodal was shown to be expressed in human breast carcinoma cell lines, but poorly expressed in normal mammary epithelial and myoepithelial cells, and intensity of Nodal staining was found to correlate with breast carcinoma progression (6). Whereas Nodal was not detected in normal melanocytes and poorly expressed in noninvasive melanoma, Nodal was robustly expressed in invasive and metastatic melanoma (2). Notch signaling has also been associated with a number of human cancers including leukemia and cancers of the colon and breast (7). However, the oncogenic role for Notch seems to be more complex. For instance, in breast cancer, Notch-2 functions as a tumor suppressor, whereas other Notch receptors are oncogenic (8); yet, in brain tumorigenesis, Notch-2 acts as an oncogene, whereas Notch-1 has the opposite effect (9). In the skin, Notch can induce cell cycle arrest and differentiation of keratinocytes (10), but promote melanocytic stem cell survival and melanoma tumorigenesis (11). Given the role for Nodal in melanoma and the observation that perturbation of Notch signaling in the skin can result in malignancies including melanoma (11), it is possible that molecular cross-talk exists between Nodal and Notch signaling in human melanoma. Evidence from developmental studies describe a role for Notch in regulating expression of Nodal that is supported by the presence of two CSL binding sites in the Node Specific Enhancer, a transcriptional regulatory region for Nodal shown to respond to Notch signaling (3).

Because Notch and Nodal signaling can be inhibited in cancer cells, preclinical and clinical studies have examined the potential for targeting Notch signaling at different points of its pathway in various Notch-expressing cancers, including breast cancer, myeloma, and leukemia (12). A commonly studied target in these studies is gamma-secretase, whose inhibitors (GSIs) can affect Notch signaling by preventing cleavage of the active NICD. For example, GSI was capable of inducing apoptosis in Notch expressing human aggressive melanoma cells but not in melanocytes (13). However, the potential for undesirable effects, given the physiologic role of gamma-secretase (or Notch signaling) in normal tissues or organs, remains a concern.

Other studies have targeted Nodal signaling pathway using small molecule ALK receptor inhibitors, or by directly inhibiting Nodal with human embryonic stem cell (hESC)-derived Lefty or anti-Nodal morpholino, and showed redifferentiation and suppression of tumorigenesis in Nodal-expressing human metastatic melanoma cells (5, 6). More recently, an anti-Nodal function blocking antibody was shown to inhibit vasculogenic mimicry of aggressive melanoma cells in vitro. Long-term exposure to the anti-Nodal antibody induced apoptosis in human melanoma cells in an in vivo mouse lung colonization assay (14). Because Nodal expression seems to be limited predominantly to cancer cells in adult tissues (5), and there is evidence for cross-talk between the Nodal and Notch signaling pathways, it may be possible to specifically target both these pathways in cancer cells in a "two-for-one" hit strategy, whereby inhibition of the Notch pathway may affect Nodal-dependent signaling and vice versa. In fact, knockdown experiments using specific Notch siRNAs showed that Notch4 knockdown was associated with reduced Nodal levels in human aggressive melanoma cells (15). Furthermore, ongoing studies from our laboratory have shown a connection between expression of Cripto-1, the Nodal co-receptor, and increased expression of Notch-4 in human melanoma cells.3

miRNA Targets and Potential Implication with Notch and Nodal Signaling and/or Function

MicroRNAs (miRNAs) are endogenous noncoding RNA sequences of ~22 nucleotides found in vertebrates and nonvertebrates capable of post-transcriptional control of gene expression by binding to specific protein-coding mRNAs (16). MicroRNA-430 (miR-430) has been shown to inhibit the translation of the zebrafish Nodal homolog squint (17). Target sites of miR-430 are detected in the mammalian Nodal gene suggesting that miRNA-dependent regulation of Nodal could occur in humans. In fact, web-based analyses of potential miRNA targets predict that members of the miR-302 cluster, the human homolog of miR-430, may regulate Nodal expression. Notch signaling is also regulated by miRNAs in mammalian cells. Specifically, miR-1 negatively affects Notch signaling by repressing the expression of the Notch ligand, Delta-like1 (18). Thus, it seems plausible that if Nodal and Notch signaling are interrelated, miRNAs capable of regulating one pathway may affect the other.

Particular miRNAs involved in tumorigenesis and progression of certain human cancers are continuously being identified. Recently, numerous miRNAs that are upregulated or downregulated in melanoma cells and specific miRNAs associated with malignant progression of melanoma have been described (19). When human melanoma cells were cultured on hESC conditioned matrix (CMTX) containing hESC-derived Lefty (Fig. 1C), the expression of Nodal in the melanoma cells was dramatically downregulated, as these cells acquired a less aggressive and more differentiated phenotype (5). This significant reduction of Nodal was also accompanied by reduced expressions of Notch4 and miR-145, and increased levels of miR-302a.4 Interestingly, miR-145 is one of several miRNAs associated with early progression of melanoma (19). In addition to potential regulation of Nodal signaling, as mentioned above, members of the miR-302 cluster have been shown to reprogram cancer cells into slowly proliferating ES-like cells, by inhibiting cell cycle regulators such as cyclin D1, a target of Notch signaling (Fig. 1A; ref. 20). Further studies will identify other candidate miRNAs induced by the stem cell microenvironment that may be involved in regulating plasticity and aggressiveness of melanoma cells by disrupting Nodal- or Notch-dependent oncogenic effects.

Significance and Implications

The importance of embryonic signaling pathways in cancer biology has gained considerable attention. Studies show that cancer cells can exploit developmental signaling pathways to facilitate proliferation and metastatic spread. Nodal and Notch are involved in normal development and have emerged as markers and mediators of tumor progression as well. Importantly, studies suggest that these critical pathways converge at the transcriptional level and that epigenetic factors, including miRNAs, may regulate the aberrant expression of these proteins. Preliminary evidence suggests that it is possible to target Nodal-expressing cancer cells with anti-Nodal function blocking antibodies. The specific expression of Nodal in cancer cells could be exploited to target delivery of anti-Notch or other therapeutics directly to cancer cells without affecting normal surrounding cells. Newly emerging technologies such as nanoparticles hold promise as delivery tools for simultaneously targeting Nodal and Notch. The identification of epigenetic and genomic alterations that facilitate the re-emergence of developmental signaling pathways and levels of potential cross-talk add a new dimension to the targeting strategy for therapeutic interventions of cancer.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

Grant support: U.S. National Institutes of Health (CA59702 and CA121205), the Eisenberg Scholar Research Award, and by the Maeve McNicholas Memorial Foundation.

We apologize to authors whose work was not directly mentioned; because of space limitations primary reviews were cited.

Footnotes

3 Personal communication.

4 Personal communication.

Received 3/31/09. Revised 5/26/09. Accepted 7/ 1/09.

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36: Emerging roles of nodal and Cripto-1: from embryogenesis to breast cancer progression.
Strizzi L, Postovit LM, Margaryan NV, Seftor EA, Abbott DE, Seftor RE, Salomon DS, Hendrix MJ.

Breast Dis. 2008;29:91-103.

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37: Off the beaten pathway: the complex cross talk between Notch and NF-kappaB.
Osipo C, Golde TE, Osborne BA, Miele LA.

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38: Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells.
Zhang XP, Zheng G, Zou L, Liu HL, Hou LH, Zhou P, Yin DD, Zheng QJ, Liang L, Zhang SZ, Feng L, Yao LB, Yang AG, Han H, Chen JY.

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39: Developmental signaling pathways in brain tumor-derived stem-like cells.
Clark PA, Treisman DM, Ebben J, Kuo JS.

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40: Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins.
Bailey JM, Singh PK, Hollingsworth MA.

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41: Tgf-Beta signaling in development.
Kitisin K, Saha T, Blake T, Golestaneh N, Deng M, Kim C, Tang Y, Shetty K, Mishra B, Mishra L.

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42: The commonality of plasticity underlying multipotent tumor cells and embryonic stem cells.
Postovit LM, Costa FF, Bischof JM, Seftor EA, Wen B, Seftor RE, Feinberg AP, Soares MB, Hendrix MJ.

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43: Metastasis and stem cell pathways.
Barnhart BC, Simon MC.

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44: Cross talk between notch and growth factor/cytokine signaling pathways in neural stem cells.
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45: Mammary stem cells and breast cancer--role of Notch signalling.
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Stem Cell Rev. 2007 Jun;3(2):169-75. Review.

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46: Signaling in adult stem cells.
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48: Selective targeting of cancer stem cells: a new concept in cancer therapeutics.
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49: Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate.
Diez H, Fischer A, Winkler A, Hu CJ, Hatzopoulos AK, Breier G, Gessler M.

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50: WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates.
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51: Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells.
Ogawa K, Saito A, Matsui H, Suzuki H, Ohtsuka S, Shimosato D, Morishita Y, Watabe T, Niwa H, Miyazono K.

J Cell Sci. 2007 Jan 1;120(Pt 1):55-65.

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52: In search of the medulloblast: neural stem cells and embryonal brain tumors.
Eberhart CG.

Neurosurg Clin N Am. 2007 Jan;18(1):59-69, viii-ix. Review.

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53: Transcriptional characterization of the Notch signaling pathway in rodent multipotent adult progenitor cells.
Hajdu M, Luttun A, Pelacho B, Burns TC, Chase L, Gutiérrez-Pérez M, Jiang Y, Lenvik T, Vas V, Uher F, Sebestyén A, Verfaillie C.

Pathol Oncol Res. 2007;13(4):302-10. Epub 2007 Dec 25.

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54: Exploiting the convergence of embryonic and tumorigenic signaling pathways to develop new therapeutic targets.
Abbott DE, Postovit LM, Seftor EA, Margaryan NV, Seftor RE, Hendrix MJ.

Stem Cell Rev. 2007 Jan;3(1):68-78. Review.

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55: Signaling pathways in cancer and embryonic stem cells.
Dreesen O, Brivanlou AH.

Stem Cell Rev. 2007 Jan;3(1):7-17. Review.

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56: Notch signaling in cancer.
Miele L, Golde T, Osborne B.

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57: Isolation and characterization of nontubular sca-1+lin- multipotent stem/progenitor cells from adult mouse kidney.
Dekel B, Zangi L, Shezen E, Reich-Zeliger S, Eventov-Friedman S, Katchman H, Jacob-Hirsch J, Amariglio N, Rechavi G, Margalit R, Reisner Y.

J Am Soc Nephrol. 2006 Dec;17(12):3300-14. Epub 2006 Nov 8.

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58: The notch signaling system is present in the postnatal pituitary: marked expression and regulatory activity in the newly discovered side population.
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59: Sustained Notch signaling in progenitors is required for sequential emergence of distinct cell lineages during organogenesis.
Zhu X, Zhang J, Tollkuhn J, Ohsawa R, Bresnick EH, Guillemot F, Kageyama R, Rosenfeld MG.

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60: NUMB is a break of WNT-Notch signaling cycle.
Katoh M, Katoh M.

Int J Mol Med. 2006 Sep;18(3):517-21.

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62: Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness.
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66: Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells.
Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH.

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67: NOTCH signaling as a novel cancer therapeutic target.
Miele L, Miao H, Nickoloff BJ.

Curr Cancer Drug Targets. 2006 Jun;6(4):313-23. Review.

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Rehman AO, Wang CY.

Trends Cell Biol. 2006 Jun;16(6):293-300. Epub 2006 May 12. Review.

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69: GDF3 at the crossroads of TGF-beta signaling.
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70: Developmental signalling pathways in lung cancer.
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72: Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells.
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74: Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells.
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77: Analysis of the interaction of extracellular matrix and phenotype of bladder cancer cells.
Dozmorov MG, Kyker KD, Saban R, Knowlton N, Dozmorov I, Centola MB, Hurst RE.

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86: Twists and turns in the development and maintenance of the mammalian small intestine epithelium.
Hauck AL, Swanson KS, Kenis PJ, Leckband DE, Gaskins HR, Schook LB.

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88: Molecular insights into prostate cancer progression: the missing link of tumor microenvironment.
Chung LW, Baseman A, Assikis V, Zhau HE.

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89: Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3.
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90: Notch and epithelial-mesenchyme transition in development and tumor progression: another turn of the screw.
Grego-Bessa J, Díez J, Timmerman L, de la Pompa JL.

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91: MAP kinase signaling in diverse effects of ethanol.
Aroor AR, Shukla SD.

Life Sci. 2004 Mar 26;74(19):2339-64. Review.

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92: Development and cancer: lessons learned in the pancreas.
Heiser PW, Hebrok M.

Cell Cycle. 2004 Mar;3(3):270-2. Epub 2004 Mar 1.

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93: Notch signaling and ERK activation are important for the osteomimetic properties of prostate cancer bone metastatic cell lines.
Zayzafoon M, Abdulkadir SA, McDonald JM.

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94: Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells.
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95: Echinoid mutants exhibit neurogenic phenotypes and show synergistic interactions with the Notch signaling pathway.
Ahmed A, Chandra S, Magarinos M, Vaessin H.

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96: Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3.
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J Cell Biol. 2003 Nov 24;163(4):723-8.

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97: Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents.
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98: Reciprocal regulatory interactions between the Notch and Ras signaling pathways in the Drosophila embryonic mesoderm.
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99: Role of phosphoinositide 3-kinase in the aggressive tumor growth of HT1080 human fibrosarcoma cells.
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100: Dissection of Ras-dependent signaling pathways controlling aggressive tumor growth of human fibrosarcoma cells: evidence for a potential novel pathway.
Gupta S, Plattner R, Der CJ, Stanbridge EJ.

Mol Cell Biol. 2000 Dec;20(24):9294-306.

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101: Epithelial cell plasticity in development and tumor progression.
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