Cancer Stem Cells in Wilms Tumor: A Targeted Strategy for NCAM+/ALDH+ Population

by Farrah A. Alkhaleel

Wilms tumor, also known as nephroblastoma, is the most common type of kidney malignancy in children with an incidence of approximately 1 in 10,000 live births [1,2]. Each year in the United States, there are approximately 500 new cases diagnosed with an annual incidence of 7 renal tumor cases per 1 million children younger than 15 years. Overall, renal malignancies account for 5% of all pediatric malignancies [3].

Most Wilms tumors are sporadic, with unknown etiology, and about 1% of patients demonstrate positive family history. Unlike retinoblastoma, the age at onset and a proportion of bilateral tumors are not significantly different for the familial and sporadic Wilm’s tumors. The vast majority, 80%, of Wilm’s tumors are diagnosed by the age of 5 years. In addition to familiar cases, several genetic syndromes, such as WAGR syndrome, Denys-Drash syndrome, and Beckwith-Wiedemann syndrome, are associated with Wilms tumors [4].

The molecular genetics of Wilm’s tumors have been intensively studied and at least three genes, WT1 (Wilms tumor-1, located in 11p13), WT2 (11p15), and WT3 (16q) were identified as tumor-suppressors implicated in the development of this disease. Specifically, a loss-of-function of the WT1 gene, encoding a zinc-finger transcription factor critical for embryonic kidney development, was found in ~ 20% of these malignancies [4]. The pathology of Wilms tumors resembles fetal kidneys, but with a morphologically disorganized architecture that includes undifferentiated metanephric precursors, suggesting incomplete kidney development. [5,6].

Studies of intra-tumoral heterogeneity of Wilms tumors’ led to the identification of a fraction of cancer stem cells (CSCs) that like normal stem cells, have the capacity for self-renewing and differentiation [7]. These CSCs are thought to be the driving force behind tumor initiation, propagation, and recurrence, and therefore, are excellent candidates for therapeutic targeting [7]. Understanding Wilms tumor development in the context of kidney embryonic development and CSC formation could better elucidate Wilms tumorigenesis and progression in this pediatric patient population.

A recent study by Benjamin Dekel laboratory from the Pediatric Stem Cell Research Institute in Tel Aviv (Israel) identified NCAM1 and ALDH1 expression as the defining markers for Wilms tumor CSCs and how these CSCs can both self-renew and differentiate to form a heterogenous tumor [8]. Indeed, Shukrun et al. showed how only 200 purified NCAM1+ALDH1+ cells injected into nude mice can initiate Wilms tumor formation and recapitulate the complex heterogeneous phenotype of the original tumor [9]. At the same time, Shukrun et al revealed that NCAM1+ALDH1− and NCAM1−ALDH1+ Wilms tumor cells have no tumorigenic potential, suggesting that Wilms tumor formation is exclusively generated by the presence of NCAM1+ALDH1+ CSCs [9]. Interestingly, Shukrun et al. also found that NCAM1+/ALDH1+ CSCs isolated from Wilms tumor can de-differentiate to a mesenchymal state, suggesting that these CSCs are early renal progenitors [9].  In fact, a recent study has shown that cell lines from Wilms tumor patients express genes that are very similar to gene expression profiles of human mesenchymal stem cells (MSCs) [10]. Specifically, MSC-specific surface proteins CD105, CD90, and CD73, were shown to be expressed on these tumor cells, indicating a consistent expression profile with potential CSCs [10].

Current treatment for Wilms tumor includes surgery, chemotherapy, and radiation, and the prognosis is greater than 90% [11]. However, there is a small subset of patients who are more prone to recurrence and resistance. Finding novel therapies such as CSC-targeting could provide a potential treatment option for these patients. Indeed, a recent pilot study investigated the correlation between the histologic characterization of NCAM+/ALDH+ CSCs with clinicopathologic parameters and prognostic outcomes. This study revealed that NCAM+/ALDH1+ Wilms’ tumor CSCs correlate with adverse clinicopathologic parameters resulting in poor clinical outcomes and disease progression [12]. Therefore, identifying and targeting these NCAM+/ALDH1+ CSCs could be used as a therapeutic strategy for Wilms tumor. Although therapeutics targeting CSCs have not yet been approved for clinical use, there are several animal studies and clinical trials that report promising findings for targeted CSC therapy. One study by Markovsky et al. successfully depleted NCAM+ CSCs by engineering an NCAM-targeted peptide and paclitaxel bound to a biodegradable polyglycolide polymer. Results of these experiments showed effective inhibition of tumor growth with limited toxicity and reduction of the NCAM-expressing cell fraction in a mouse model consisting of a human Wilms tumor patient-derived xenograft [13]. Other studies have shown promising results using anti-NCAM antibody-drug conjugate in effectively depleting Wilms tumor CSCs both using xenograft-derived Wilms tumor cell cultures and Wilms tumor xenograft mouse models [14]. Overall, nano-targeting of NCAM+ CSCs as a combined regimen with standard chemotherapy and radiation offers a potential therapeutic avenue in pediatric Wilms tumor patients with recurrent malignancy and drug resistance.

References:

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