Abstract
Hepatoblastoma (HB) is the most common malignant liver tumor that occurs during childhood. The prognosis of children with HB is favorable when a complete surgical resection of the tumor is possible, but for high-risk patients, the prognosis is much worse. New anti-HB strategies must be urgently developed. The undecapeptide substance P (SP) after binding to the neurokinin-1 receptor (NK-1R), regulates cancer cell proliferation, exerts an antiapoptotic effect, induces cell migration for invasion/metastasis, and triggers endothelial cell proliferation for neoangiogenesis. HB samples and cell lines overexpress NK-1R (the truncated form) and SP elicits HB cell proliferation. One of these strategies could be the use of non-peptide NK-1R antagonists. These antagonists exert, in a concentration-dependent manner, an antiproliferative action against HB cells (inhibit cell proliferation and induce the death of HB cells by apoptosis). NK-1R antagonists exerted a dual effect in HB: Decreased both tumor volume and angiogenic activity. Thus, the SP/NK-1R system is an important target in the HB treatment and NK-1R antagonists could act as specific drugs against HB cells. In this review, we update and discuss the use of NK-1R antagonists in the treatment of HB.
Highlights
Hepatoblastoma (HB) is the most frequent primary malignant liver tumor in children
In 47 children with HB, it was reported that the tr-TACR1 isoform was expressed ubiquitously among the different subsets of HB (Table 2). This finding is important since the neurokinin-1 receptor (NK-1R) may serve as a therapeutic target in HB patients, independent of the clinical stage/tumor biology [32]
It is known that substance P (SP) promotes the migration of tumor cells (SP favors the formation of membrane blebbing) for invasion/metastasis; that SP increased the expression of VEGF-C and matrix metalloproteinase favoring tumor metastasis; that NK-1R antagonists inhibit such an increase [70,71], and that these antagonists block the changes in the cell shape induced by SP (in the latter mechanisms Rho-associated protein kinase (ROCK) was involved) (Figure 1) [72]
Summary
Hepatoblastoma (HB) is the most frequent primary malignant liver tumor in children (generally between six months to three years). Human tumor cells (including HB) overexpress NK-1R, this receptor being involved in the viability of these cells; this means that NK-1R can be considered a new tumor marker [4,5,6] This is crucial, since it is well known that NK-1R antagonists (currently, there are more than 300 compounds: Such as the drug aprepitant, L-732,138, L-733,060) exert multiple antitumor activities (antiproliferative, apoptotic effect, antimigration, antiangiogenesis) [7]. This pathway is involved in cell proliferation and survival and it is activated via the receptor tyrosine kinase, which can be activated by cytokines or the epidermal growth factor (Figure 1) [12] The activation of this pathway (crucial to drug resistance) promotes the activation, through phosphorylation, of many intracellular proteins. The data suggest that the PI3K/Akt/mTOR signaling pathway (Figure 1) plays a crucial role in the HB growth inhibition exerted by NK-1R antagonists
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