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

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.

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

“…The apparent loss of Cripto gene expression in adult tissues might reflect the rarity of the cells expressing it, rather than its absence per se [ 13 ]. In humans, CRIPTO distribution appears restricted to stem cell niches and the small subpopulation of adult somatic cells, being implicated in stem cell compartment of hierarchically organized tissues (i.e., hematopoietic system, gastrointestinal epithelium), in normal cyclic regenerative processes as well as in injury/regeneration settings [ 13 ]. CRIPTO protein is also detectable in the serum of the majority of individuals in a population-based sample [ 14 ].…”

“…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 ].…”

“…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 ]. On the other side, CRIPTO is also able to induce many tumorigenic features, such as Epithelial-Mesenchymal transition (EMT), tumor cell proliferation, migration, and tumor neovascularization [ 15 , 17 ].…”

CRIPTO Is a Marker of Chemotherapy-Induced Stem Cell Expansion in Non-Small Cell Lung Cancer

“…CRIPTO is an obligate co-receptor for the TGF-β family members Nodal and GDF1/3 implicated in development, pluripotency and cancer ( 3 – 5 ). Besides its well-known role as modulator of TGF-β signaling, CRIPTO also cooperates with different pathways including WNT, AKT and NOTCH ( 6 ). CRIPTO is overexpressed in several human tumors including breast, colorectal, lung, renal, ovarian, pancreatic, prostate, gastric, bladder and esophageal cancers, melanoma and glioblastoma ( 7 – 19 ).…”

CRIPTO promotes extracellular vesicle uptake and activation of cancer associated fibroblasts

“…CRIPTO is a small GPI-anchored signaling protein encoded by the TDGF1 gene that balances TGF-β singaling and independent pathways that activate c-Src/MEK/AKT [2][3][4] . It is prominently expressed in stem cells and early development, largely undetectable in adult homeostatic tissue, but reexpressed in the context of oncogenesis and wound healing 4 .…”