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 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.
Highlights
Epigraphs “Elements which have retained their [ . . . ] embryonal characteristics in the adult organism or have regained them through some chemico-physiologic deviation, represent [. . . ] the generative elements of every tumor variety and those of a malignant nature
Much has been learned about CRIPTO in recent years, it has continued to live up to its name, which was assigned over 30 years ago when CRIPTO was discovered as an oncogene with unknown function
While directed analysis has revealed CRIPTO to be a stem cell regulatory factor that is frequently re-emergent in diverse cancers and concordantly shown it to be a clinically relevant biomarker of disease progression, unsupervised studies rarely identify CRIPTO and it remains difficult to detect in many settings where its ablation and blockade show significant effects
Summary
Epigraphs “Elements which have retained their [ . . . ] embryonal characteristics in the adult organism or have regained them through some chemico-physiologic deviation, represent [. 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 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
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