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Advances in Radiotherapy
& Nuclear Medicine Cripto-1 in cancer diagnosis and therapy

these approaches often have limited efficacy in patients (C1 – C4, C3 – C5, C2 – C6). Proper folding of this
7,8
with advanced or treatment-resistant tumors and are domain is driven by the formation of the C3 – C5 bridge,
associated with significant side effects, which seriously supported by residues within the segment. This domain
impact patients’ quality of life. Consequently, identifying is particularly important for receptor recognition and is
novel tumor therapeutic targets and developing more central to Cripto-1’s function. The C-terminal is anchored
effective and safer treatment strategies remain critical to the plasma membrane through a GPI moiety, whereas
challenges in cancer research. the N-terminal signal peptide facilitates intracellular
6,9
Cripto-1, also known as teratocarcinoma-derived transport and ensures appropriate cellular localization.
growth factor 1, has emerged as a key molecule in both This structural organization enables Cripto-1 to exist in
embryonic development and tumor progression. As a two distinct forms: A membrane-bound form and a soluble
member of the epidermal growth factor (EGF)-Cripto- secretory form. When ligands or signal molecules bind
1-FRL-1-Cryptic (CFC) family, Cripto-1 is a small, to membrane-bound Cripto-1, a conformational change
2
glycosylphosphatidylinositol (GPI)-anchored oncofetal occurs, activating intracellular signaling pathways that
protein that plays essential roles in stem cell differentiation, regulate gene expression and cellular functions. Multiple
embryogenesis, tissue growth, and remodeling. Recent studies have demonstrated that membrane-bound Cripto-1
3,4
studies have demonstrated that Cripto-1 is aberrantly is involved in the early stages of carcinogenesis, as well as
10
overexpressed in various tumor tissues and is closely in promoting tumor growth, survival, and metastasis.
associated with tumor initiation, progression, invasion, In addition, Cripto-1 can be detected in the bloodstream
and metastasis. It regulates critical biological processes in a soluble form, where it retains biological activity and
such as tumor cell proliferation, differentiation, and exerts systemic effects on target cells, contributing to both
apoptosis while also contributing to tumor angiogenesis physiological and pathological processes. 11
and immune evasion. These findings highlight Cripto-1 Cripto-1 functions as a molecular bridge between
as a promising target for cancer diagnosis and therapy. Nodal and the type I receptor activin receptor-like
A deeper understanding of its role in tumorigenesis 12
may offer novel strategies for early diagnosis, prognosis kinase 4 (ALK4), utilizing distinct structural domains.
assessment, and precision oncology. Unlike canonical transforming growth factor (TGF)-β
signaling, in which the type II receptor directly recruits
We conducted a PubMed search using “Cripto-1” as the type I receptor, Nodal relies on Cripto-1 to facilitate
the primary keyword, covering publications from 1990 to the formation of a ternary complex with ALK4, enabling
2025. Our focus was on studies reporting novel findings SMAD2/3 activation. This unique mechanism, rooted
on the diagnostic and therapeutic relevance of Cripto-1, in the specific structural features of Cripto-1, is vital
particularly those published in the past 5 years. While during embryogenesis, including germ layer formation,
previous reviews have comprehensively summarized the development of organs such as the heart, nervous system,
molecular structure and mechanisms of Cripto-1 in several and reproductive system, and maintaining proper cellular
cancers (e.g., breast, liver, lung, colon, prostate, kidney, functions. 13-17 Conditional inactivation of Cripto-1 during
and melanoma), we deliberately minimized these aspects gastrulation leads to abnormal mesoderm and endoderm
to avoid redundancy. Instead, we focused on gliomas and specification, while complete genetic ablation or ectopic
head and neck cancers (HNC), where emerging evidence overexpression in mice results in embryonic lethality, 18,19
highlights new perspectives on the clinical potential of underscoring the need for tightly regulated Cripto-1
Cripto-1.
expression during development. Furthermore, Cripto-1 is
2. The structure of Cripto-1 and its involved in the morphogenesis of multiple organs. In the
relationship with tumors mouse mammary gland, Cripto-1 plays a pivotal role in
alveolar development. Its deletion impairs alveologenesis
2.1. Structure and regulation of Cripto-1 expression through a progesterone receptor-mediated mechanism.
20
Cripto-1 is composed of four primary domains: An While Cripto-1 is not required for the initial elongation
N-terminal signal peptide, an EGF-like domain, a of mammary ducts, it is indispensable for side-branching
CFC domain, and a hydrophobic C-terminal domain morphogenesis and alveologenesis during early pregnancy,
containing the GPI anchorage and cleavage signal. The demonstrating its stage-specific function in organogenesis.
5
EGF-like domain contains conserved amino acid motifs In contrast to its dynamic expression during development,
and secondary structural elements facilitating specific Cripto-1 is minimally expressed or undetectable in most
interactions with ligands or other proteins. The CFC adult tissues, where its tightly regulated expression is
6
domain exhibits a unique pattern of disulfide bridges thought to contribute to tissue homeostasis. 21

Volume 3 Issue 3 (2025) 84 doi: 10.36922/ARNM025130015