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Nodal and Cripto-1 Signaling: Re-emergence in Cancer and Biological Role
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Nodal and Cripto-1 Signaling: Re-emergence in Cancer and Biological Role

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 14157

Special Issue Editor

Dr. Luigi Strizzi

E-Mail Website
Guest Editor
Department of Pathology, Midwestern University, Downers Grove, IL, USA
Interests: cancer biomarkers; therapeutic targets
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The heterogeneous nature of cancer is exemplified by metastatic lesions that do not resemble the original primary cancer and by disease recurrence in patients that initially showed therapeutic response. The identification of stem-cell-like cancer cells (CSCs) that presumably generate the diverse progeny of cancer cells is thought to contribute to this heterogeneity. Thus, efforts continue towards identifying specific markers for detecting and targeting these CSCs. A more functional approach for clarifying the biological role of these CSCs is to study the re-emergence of embryonic signaling pathways in cancer. Nodal, a tumor growth factor-beta-related protein, and its co-receptor Cripto-1, a member of the epidermal growth factor-like family of proteins, are both important for embryonic development. Both these proteins are also re-expressed in different cancer types and have been shown to play a role in cancer progression, plasticity and transdifferentiation, and drug resistance. The aim of this Special Issue is to highlight some of the key findings that support the role of Nodal and Cripto-1 during these processes and how these results may be exploited for the development of novel biomarkers and therapeutic targets.

Dr. Luigi Strizzi
Guest Editor

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Keywords

  • Nodal
  • Cripto-1
  • proliferation
  • drug resistance
  • biomarker
  • therapeutic targets

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Published Papers (4 papers)

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Research

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12 pages, 2079 KiB  
Article
Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity
by Gustavo Untiveros, Lindsay Dezi, Megan Gillette, Julia Sidor and Luigi Strizzi
Int. J. Mol. Sci. 2021, 22(21), 11719; https://doi.org/10.3390/ijms222111719 - 29 Oct 2021
Cited by 4 | Viewed by 2227
Abstract
Melanoma is a lethal form of skin cancer triggered by genetic and environmental factors. Excision of early-stage, poorly aggressive melanoma often leads to a successful outcome; however, left undiagnosed these lesions can progress to metastatic disease. This research investigates whether the exposure of [...] Read more.
Melanoma is a lethal form of skin cancer triggered by genetic and environmental factors. Excision of early-stage, poorly aggressive melanoma often leads to a successful outcome; however, left undiagnosed these lesions can progress to metastatic disease. This research investigates whether the exposure of poorly aggressive melanoma to certain normal skin cells can explain how non-metastatic melanoma becomes more aggressive while still confined to the skin. To this end, we used a serial co-culture approach to sequentially expose cells from two different, poorly aggressive human melanoma cell lines against normal cells of the skin beginning with normal melanocytes, then epidermal keratinocytes, and finally dermal fibroblasts. Protein extraction of melanoma cells occurred at each step of the co-culture sequence for western blot (WB) analysis. In addition, morphological and functional changes were assessed to detect differences between the serially co-cultured melanoma cells and non-co-cultured cells. Results show that the co-cultured melanoma cells assumed a more mesenchymal morphology and displayed a significant increase in proliferation and invasiveness compared to control or reference cells. WB analysis of protein from the co-cultured melanoma cells showed increased expression of Snail and decreased levels of E-cadherin suggesting that epithelial-to-mesenchymal transition (EMT) is occurring in these co-cultured cells. Additional WB analysis showed increased levels of Nodal protein and signaling and signs of increased Wnt activity in the co-cultured melanoma cells compared to reference cells. These data suggest that interaction between poorly aggressive melanoma cells with normal cells of the skin may regulate the transition from localized, poorly aggressive melanoma to invasive, metastatic disease via Nodal and/or Wnt induced EMT. Full article
(This article belongs to the Special Issue Nodal and Cripto-1 Signaling: Re-emergence in Cancer and Biological Role)
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Review

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31 pages, 8268 KiB  
Review
Whence CRIPTO: The Reemergence of an Oncofetal Factor in ‘Wounds’ That Fail to Heal
by David W. Freeman, Elisa Rodrigues Sousa, Sofia Karkampouna, Eugenio Zoni, Peter C. Gray, David S. Salomon, Marianna Kruithof-de Julio and Benjamin T. Spike
Int. J. Mol. Sci. 2021, 22(18), 10164; https://doi.org/10.3390/ijms221810164 - 21 Sep 2021
Cited by 6 | Viewed by 4142
Abstract
There exists a set of factors termed oncofetal proteins that play key roles in ontogeny before they decline or disappear as the organism’s tissues achieve homeostasis, only to then re-emerge in cancer. Although the unique therapeutic potential presented by such factors has been [...] Read more.
There exists a set of factors termed oncofetal proteins that play key roles in ontogeny before they decline or disappear as the organism’s tissues achieve homeostasis, only to then re-emerge in cancer. Although the unique therapeutic potential presented by such factors has been recognized for more than a century, their clinical utility has yet to be fully realized1. This review highlights the small signaling protein CRIPTO encoded by the tumor derived growth factor 1 (TDGF1/Tdgf1) gene, an oft cited oncofetal protein whose presence in the cancer literature as a tumor promoter, diagnostic marker and viable therapeutic target continues to grow. We touch lightly on features well established and well-reviewed since its discovery more than 30 years ago, including CRIPTO’s early developmental roles and modulation of SMAD2/3 activation by a selected set of transforming growth factor β (TGF-β) family ligands. We predominantly focus instead on more recent and less well understood additions to the CRIPTO signaling repertoire, on its potential upstream regulators and on new conceptual ground for understanding its mode of action in the multicellular and often stressful contexts of neoplastic transformation and progression. We ask whence it re-emerges in cancer and where it ‘hides’ between the time of its fetal activity and its oncogenic reemergence. In this regard, we examine CRIPTO’s restriction to rare cells in the adult, its potential for paracrine crosstalk, and its emerging role in inflammation and tissue regeneration—roles it may reprise in tumorigenesis, acting on subsets of tumor cells to foster cancer initiation and progression. We also consider critical gaps in knowledge and resources that stand between the recent, exciting momentum in the CRIPTO field and highly actionable CRIPTO manipulation for cancer therapy and beyond. Full article
(This article belongs to the Special Issue Nodal and Cripto-1 Signaling: Re-emergence in Cancer and Biological Role)
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12 pages, 1026 KiB  
Review
Cripto-1 as a Key Factor in Tumor Progression, Epithelial to Mesenchymal Transition and Cancer Stem Cells
by Hilal Arnouk, Gloria Yum and Dean Shah
Int. J. Mol. Sci. 2021, 22(17), 9280; https://doi.org/10.3390/ijms22179280 - 27 Aug 2021
Cited by 9 | Viewed by 3891
Abstract
Cripto-1 is an essential protein for human development that plays a key role in the early phase of gastrulation in the differentiation of an embryo as well as assists with wound healing processes. Importantly, Cripto-1 induces epithelial to mesenchymal transition to turn fixed [...] Read more.
Cripto-1 is an essential protein for human development that plays a key role in the early phase of gastrulation in the differentiation of an embryo as well as assists with wound healing processes. Importantly, Cripto-1 induces epithelial to mesenchymal transition to turn fixed epithelial cells into a more mobile mesenchymal phenotype through the downregulation of epithelial adhesion molecules such as E-cadherin, occludins, and claudins, and the upregulation of mesenchymal, mobile proteins, such as N-cadherin, Snail, and Slug. Consequently, Cripto-1’s role in inducing EMT to promote cell motility is beneficial in embryogenesis, but detrimental in the formation, progression and metastasis of malignant tumors. Indeed, Cripto-1 is found to be upregulated in most cancers, such as breast, lung, gastrointestinal, hepatic, renal, cervical, ovarian, prostate, and skin cancers. Through its role in EMT, Cripto-1 can remodel cancer cells to enable them to travel through the extracellular matrix as well as blood and lymphatic vessels to metastasize to different organs. Additionally, Cripto-1 promotes the survival of cancer stem cells, which can lead to relapse in cancer patients. Full article
(This article belongs to the Special Issue Nodal and Cripto-1 Signaling: Re-emergence in Cancer and Biological Role)
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14 pages, 8689 KiB  
Review
New Insights into Cancer Targeted Therapy: Nodal and Cripto-1 as Attractive Candidates
by Paola Arboretto, Michele Cillo and Antonio Leonardi
Int. J. Mol. Sci. 2021, 22(15), 7838; https://doi.org/10.3390/ijms22157838 - 22 Jul 2021
Cited by 2 | Viewed by 2883
Abstract
The transforming growth factor beta (TGF-β) signaling is fundamental for correct embryonic development. However, alterations of this pathway have been correlated with oncogenesis, tumor progression and sustaining of cancer stem cells (CSCs). Cripto-1 (CR-1) and Nodal are two embryonic proteins involved in TGF-β [...] Read more.
The transforming growth factor beta (TGF-β) signaling is fundamental for correct embryonic development. However, alterations of this pathway have been correlated with oncogenesis, tumor progression and sustaining of cancer stem cells (CSCs). Cripto-1 (CR-1) and Nodal are two embryonic proteins involved in TGF-β signaling. Their expression is almost undetectable in terminally differentiated cells, but they are often re-expressed in tumor cells, especially in CSCs. Moreover, cancer cells that show high levels of CR-1 and/or Nodal display more aggressive phenotypes in vitro, while in vivo their expression correlates with a worse prognosis in several human cancers. The ability to target CSCs still represents an unmet medical need for the complete eradication of certain types of tumors. Given the prognostic role and the selective expression of CR-1 and Nodal on cancer cells, they represent archetypes for targeted therapy. The aim of this review is to clarify the role of CR-1 and Nodal in cancer stem populations and to summarize the current therapeutic strategy to target CSCs using monoclonal antibodies (mAbs) or other molecular tools to interfere with these two proteins. Full article
(This article belongs to the Special Issue Nodal and Cripto-1 Signaling: Re-emergence in Cancer and Biological Role)
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