Page 93 - ARNM-3-3

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

Mechanistically, Cripto-1 not only acts as a co-receptor activation of TGF-β1 and Nodal signaling and inhibits
for Nodal-mediated SMAD2/3 activation but also downstream c-Src, Erk/MAPK, and PI3K/Akt pathways,
triggers the c-Src/MAPK/AKT signaling cascade in a suggesting that this interaction is essential for Cripto-
Glypican-1 and GRP78-dependent manner. Moreover, 1’s oncogenic functions. Moreover, Cripto-1 binding to
Cripto-1 engages in cross-talk with key signaling GRP78 promotes SMAD2/3 phosphorylation, further
pathways such as Wnt/β-catenin, notch, and hypoxia- regulating tumor cell proliferation. Both Cripto-1
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inducible factor-1α, integrating into a complex signaling and GRP78 are often overexpressed in various human
network that orchestrates cellular processes relevant to malignancies, and their interaction may synergistically
both development and disease. 22-25 Cripto-1 expression is enhance stem-like properties, tumor invasiveness, cellular
regulated at multiple levels. At the transcriptional level, plasticity, and therapy resistance. In addition to these
its promoter contains SMAD-binding elements, hypoxia roles, Cripto-1 functions as a chaperone for low-density
response elements, and T cell factor/lymphoid enhancer lipoprotein receptor-related protein 5 and 6 (LRP5/6),
factor-binding sites that mediate regulation by various promoting the activation of the canonical Wnt/β-catenin
transcription factors. 25-27 Epigenetically, DNA methylation signaling pathway. The cross-talk between Cripto-1-
influences Cripto-1 expression. Post-transcriptionally, mediated Nodal-dependent and Nodal-independent
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microRNAs regulate Cripto-1 messenger RNA stability signaling pathways is illustrated in Figure 1. A growing
and translational efficiency. 29-31 body of evidence supports the central role of Cripto-1 in
regulating tumor progression and mediating therapeutic
2.2. Relationship between Cripto-1 and tumors resistance. 22,32
Cripto-1 exhibits oncogenic properties, with its persistent Metastasis, a hallmark of malignancy, represents a
or elevated expression playing a pivotal role in cancer pivotal step in tumor progression and is the leading cause
progression. Its expression is significantly higher in breast of cancer-related mortality and treatment failure. Most
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cancer, colon cancer, hepatocellular carcinoma (HCC), and cancer patients succumb to metastatic disease rather than
pre-cancerous lesions compared to corresponding normal to the primary tumor. In epithelial-derived malignancies,
tissues. Expression of Cripto-1 follows a progressive pattern, tumor cells often undergo EMT – a process characterized
increasing from normal tissues to pre-cancerous stages and by the loss of intercellular adhesion, acquisition of a
ultimately contributing to multistage tumor formation. mesenchymal, fibroblast-like phenotype, and enhanced
Extensive studies have demonstrated the essential role of migratory and invasive capacities – facilitates tumor
Cripto-1 in diverse cancer types, implicating it not only cell dissemination and confers stem cell-like properties,
in tumor growth but also in processes such as epithelial- thereby increasing tumor aggressiveness and metastatic
mesenchymal transition (EMT) and the regulation of potential. While EMT is a physiological process essential
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cancer stem cells (CSCs). 32 for embryogenesis, tissue regeneration, and wound healing,
2.2.1 Mechanisms of cripto-1 in tumor development its aberrant activation is a key driver of malignant tumor
Cripto-1 plays a critical role in promoting tumor cell
proliferation, migration, EMT, and the maintenance of
CSCs through multiple signal pathways. These include
both Nodal-dependent SMAD2/3 activation and Nodal-
independent pathways such as Src, Ras/Raf/MAPK, and
PI3K/Akt signaling. Distinct structural domains of the
Cripto-1 protein mediate interactions with various binding
partners, facilitating its role in signal transduction. The EGF-
like domain binds to Nodal to regulate its activity, whereas
the CFC domain interacts with GRP78 and ALK4. Notably,
both signaling pathways rely on GRP78, an endoplasmic
reticulum chaperone that regulates the degradation of
misfolded proteins through the ubiquitin-proteosome
system. GRP78 is highly expressed on the surface of stem
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cells and tumor cells, and its elevated levels are strongly Figure 1. Cross-talk between Cripto-1-mediated Nodal-dependent and
associated with enhanced tumor growth, malignancy, Nodal-independent signaling pathways
Abbreviations: ALK4: Activin receptor-like kinase 4; EMT: Epithelial-
and therapy resistance. 33,34 Competitive inhibition of the mesenchymal transition; LRP: low-density lipoprotein receptor-related
Cripto-1/GRP78 interaction disrupts Cripto-1-mediated protein; P: Phosphorylated.

Volume 3 Issue 3 (2025) 85 doi: 10.36922/ARNM025130015