A Multidisciplinary Review of the Roles of Cripto in the Scientific Literature Through a Bibliometric Analysis of its Biological Roles

Abstract

Cripto is a small glycosylphosphatidylinisitol (GPI)-anchored and secreted oncofetal protein that plays important roles in regulating normal physiological processes, including stem cell differentiation, embryonal development, and tissue growth and remodeling, as well as pathological processes such as tumor initiation and progression. Cripto functions as a co-receptor for TGF-β ligands such as Nodal, GDF1, and GDF3. Soluble and secreted forms of Cripto also exhibit growth factor-like activity and activate SRC/MAPK/PI3K/AKT pathways. Glucose-Regulated Protein 78 kDa (GRP78) binds Cripto at the cell surface and has been shown to be required for Cripto signaling via both TGF-β and SRC/MAPK/PI3K/AKT pathways. To provide a comprehensive overview of the scientific literature related to Cripto, we performed, for the first time, a bibliometric analysis of the biological roles of Cripto as reported in the scientific literature covering the last 10 years. We present different fields of knowledge in comprehensive areas of research on Cripto, ranging from basic to translational research, using a keyword-driven approach. Our ultimate aim is to aid the scientific community in conducting targeted research by identifying areas where research has been conducted so far and, perhaps more importantly, where critical knowledge is still missing.

Canonical TGFβ Signaling and Its Contribution to Endometrial Cancer Development and Progression—Underestimated Target of Anticancer Strategies

“…To date, a few molecules have been identified and described as acting as TGFβ co-receptors, including betaglycan (TGFβR3), endoglin (CD105), CD109, and repulsive guidance molecules a-c (RGMa, RGMb, RGMc), in general, well-known and extensively studied TGFβ receptors type III [18,[154][155][156][157]. Recently however, the term "TGFβ coreceptors" has been modified, as there have been described novel proteins or cellular components modulating TGFβ response, as well as providing possible ways for integration of TGFβ canonical pathway with the other signaling cascades.…”

“…Among the above-mentioned TGFβ co-receptors, only betaglycan, endoglin and CD109 participate in a modulation of the signal induced by three TGFβ isoforms. Although, betaglycan and endoglin are not only structurally related but also of the highest importance for cancer development and progression [18,[154][155][156][157][158] (Figure 4A). Betaglycan was the first identified molecule with an assigned function as a TGFβ co-receptor [159].…”

A Novel Localization in Human Large Extracellular Vesicles for the EGF-CFC Founder Member CRIPTO and Its Biological and Therapeutic Implications

“…CRIPTO protein is also detectable in the serum of the majority of individuals in a population-based sample [ 14 ]. High CRIPTO expression levels, instead, have been related to tumorigenesis and poor prognosis in an increasing number of cancers, as for example, melanoma, breast, lung, esophageal, gastric, colon, hepatocellular, pancreatic, renal, prostate, and bladder carcinomas [ 13 , 15 , 16 ]. In many of these, CRIPTO expression has been mainly detected in cancer stem cells (CSCs), suggesting its role in CSC compartment regulation [ 13 ].…”

Whence CRIPTO: The Reemergence of an Oncofetal Factor in ‘Wounds’ That Fail to Heal

“…This review highlights the small signaling protein CRIPTO (CRIPTO-1; CR-1; TDGF1) 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 [ 3 , 4 , 5 , 6 , 7 ]) 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.…”