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

progression. Cripto-1 contributes to EMT by modulating Cripto-1 expression is correlated with shorter survival
the expression of epithelial and mesenchymal markers and in younger patients. Pilgaard et al. further reported
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promoting cytoskeletal reorganization. In breast cancer, that elevated plasma levels of Cripto-1 in GBM patients
Cripto-1 overexpression enhances cell migration and are significantly associated with reduced OS. The
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invasion through EMT, whereas its inhibition suppresses proliferation and survival of GBM cells are regulated by
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these processes. Notably, Cripto-1 can induce EMT and various signaling molecules, including Src, focal adhesion
promote proliferation independently of the Nodal pathway, kinase, c-Jun, and paxillin. However, studies investigating
primarily through activation of the c-Src/MAPK/AKT the mechanistic role of Cripto-1 in GBM remain limited.
signaling cascade in a Glypican-1-dependent manner. In Alowaidi et al. were the first to demonstrate the direct
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addition, Cripto-1 activates other key signaling pathways, influence of Cripto-1 on EMT markers such as Vimentin
including Wnt/β-catenin and TGF-β, further reinforcing and Twist in the U87 GBM cell line. Cripto-1 overexpression
EMT in tumor cells. enhanced the migratory and invasive capabilities of
During tumor progression, EMT also plays a crucial U87 cells and demonstrated functional similarity to SOX2
role in the acquisition of CSC characteristics, which are in maintaining CSC-like properties. Kyoto Encyclopedia
linked to stemness, therapy resistance, and high metastatic of Genes and Genomes pathway analysis revealed that
Cripto-1 stimulation alters protein phosphorylation across
capacity. The dysregulation of developmental pathways 47 signaling pathways, particularly those involving ErbB,
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governing EMT and stem cell self-renewal is a common MAPK, and focal adhesion signaling. These findings
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feature of many cancers. Cripto-1, which is highly expressed indicate that Cripto-1 promotes EMT and stemness
in embryonic stem cells, contributes to CSC maintenance in GBM, suggesting its potential as both a prognostic
across various malignancies. 40,41 For instance, in esophageal biomarker and a therapeutic target.
squamous cell carcinoma, Cripto-1 knockdown reduces
EMT-related gene expression, diminishes stemness, and 2.2.3. Cripto-1 and HNC
impairs self-renewal and metastatic potential. In HCC,
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Cripto-1 promotes proliferation, migration, invasion, and HNC represents a diverse group of malignancies, with head
chemoresistance by regulating the Wnt/β-catenin pathway and neck squamous cell carcinoma accounting for over
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and enhancing CSC-like characteristics. Moreover, 90% of all cases. HNC primarily arises from the mucosal
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Cripto-1 is implicated in angiogenesis and in regulating epithelial cells of the upper respiratory and digestive tracts,
the motility and invasiveness of glioblastoma cells. 44,45 commonly affecting the oral cavity, oropharynx, larynx,
Collectively, these findings suggest that Cripto-1 sustains and hypopharynx. Current treatments include surgical
CSC self-renewal and stemness by inducing EMT and resection, radiotherapy, chemotherapy, targeted therapy,
activating multiple oncogenic signaling pathways. Its and immunotherapy. Despite significant advancements
aberrant expression and interactions in CSCs contribute in therapeutic approaches, HNC continues to exhibit
high rates of recurrence and mortality, with minimal
to EMT progression, therapy resistance, and metastatic improvement in the overall 5-year survival rate.
dissemination.
Nasopharyngeal cancer (NPC) is an epithelial
Arnouk et al. comprehensively reviewed the
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regulatory role of Cripto-1 in breast, lung, liver, prostate, malignancy originating in the upper and lateral walls of
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renal, reproductive, and skin cancers. More recent studies the nasopharyngeal cavity. Due to its deep anatomical
have extended its relevance to gliomas and head and neck location and subtle early symptoms, NPC is often
tumors. diagnosed at an advanced stage, frequently accompanied
by invasion and metastasis. Cripto-1 is highly expressed
2.2.2. Cripto-1 and glioblastoma multiforme (GBM) in tumor tissue samples from nasopharyngeal carcinoma
(NPC) patients, and its expression level is significantly
GBM is the most common primary brain tumor, with a associated with distant metastasis and clinical staging of
median overall survival (OS) of 12–15 months. 46,47 GBM NPC. Cripto-1 also exhibits high expression in cultured
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exhibits aggressive and infiltrative growth, frequently NPC cells in vitro. Functional assays showed that Cripto-1
crossing the corpus callosum and affecting multiple cerebral knockdown significantly inhibited NPC cell proliferation
hemispheres, particularly the frontal lobes. It is characterized and invasion in vitro. Furthermore, Cripto-1 was found
by rapid progression, diffuse invasion, and resistance to to be co-expressed with the oncogene latent membrane
existing therapies, in contrast to low-grade astrocytoma, protein 1 (LMP1) in NPC tissues, suggesting a cooperative
which often follows a more indolent disease course. 48 role in promoting tumor progression and metastasis. 54
Cripto-1 protein levels are significantly elevated in Oral and maxillofacial malignancies comprise 4.7 – 20.5%
tissue samples from patients with primary GBM, and high of all HNCs, with oral squamous cell carcinoma (OSCC)

Volume 3 Issue 3 (2025) 86 doi: 10.36922/ARNM025130015