Chemotherapy and terminal skeletal muscle differentiation in WT1‐mutant Wilms tumors

Abstract

Wilms tumors (WT) with WT1 mutations do not respond well to preoperative chemotherapy by volume reduction, suggesting resistance to chemotherapy. The histologic pattern of this tumor subtype indicates an intrinsic mesenchymal differentiation potential. Currently, it is unknown whether cytotoxic treatments can induce a terminal differentiation state as a direct comparison of untreated and chemotherapy‐treated tumor samples has not been reported so far. We conducted gene expression profiling of 11 chemotherapy and seven untreated WT1‐mutant Wilms tumors and analyzed up‐ and down‐regulated genes with bioinformatic methods. Cell culture experiments were performed from primary Wilms tumors and genetic alterations in WT1 and CTNNB1 analyzed. Chemotherapy induced MYF6 165‐fold and several MYL and MYH genes more than 20‐fold and repressed many genes from cell cycle process networks. Viable tumor cells could be cultivated when patients received less than 8 weeks of chemotherapy but not in two cases with longer treatments. In one case, viable cells could be extracted from a lung metastasis occurring after 6 months of intensive chemotherapy and radiation. Comparison of primary tumor and metastasis cells from the same patient revealed up‐regulation of RELN and TBX2,TBX4 and TBX5 genes and down‐regulation of several HOXD genes. Our analyses demonstrate that >8 weeks of chemotherapy can induce terminal myogenic differentiation in WT1‐mutant tumors, but this is not associated with volume reduction. The time needed for all tumor cells to achieve the terminal differentiation state needs to be evaluated. In contrast, prolonged treatments can result in genetic alterations leading to resistance.

Prognostic Factors for Wilms Tumor Recurrence: A Review of the Literature

“…Tumor volume after pre-operative chemotherapy also predicted tumor recurrence in local blastemal-type WT [83]. Tumors with WT1 mutations do not show volume reduction after chemotherapy, which is thought to be due to chemotherapy-induced skeletal muscle cell differentiation rather than apoptotic cell death [90,91]. However, as we will discuss in more detail in Section 7, germline and somatic WT1 mutations are not independently associated with an increased risk of tumor recurrence.…”

The depletion of Circ‐PRKDC enhances autophagy and apoptosis in T‐cell acute lymphoblastic leukemia via microRNA‐653‐5p/Reelin mediation of the PI3K/AKT/mTOR signaling pathway

“…32 Moreover, previous research has shown that RELN expression is dramatically elevated in Wilms' tumor and encodes the secreted extracellular matrix protein to modulate cell interactions and migration. 33 Mechanistically, the depletion of RELN functions to impede the aggressive actions of non-Hodgkin lymphoma cells and induces G0/G1 phase arrest and apoptosis. 34 The overexpression of RELN has also been detected in prostate cancer; miR-381-mediated RELN inhibition is capable of enhancing cell apoptosis and autophagy by inactivating the PI3K/AKT/mTOR signaling pathway.…”

“…Due to hypomethylation in the promoter region, the expression of RELN is elevated in multiple myeloma 32 . Moreover, previous research has shown that RELN expression is dramatically elevated in Wilms' tumor and encodes the secreted extracellular matrix protein to modulate cell interactions and migration 33 . Mechanistically, the depletion of RELN functions to impede the aggressive actions of non‐Hodgkin lymphoma cells and induces G0/G1 phase arrest and apoptosis 34 .…”

Desenvolvimento De Protocolo De Intervenção Farmacêutica Para O Tratamento Do Tumor De Wilms

“…A prescrição da medicação de suporte, também é fundamental para evitar tais efeitos adversos. Isso demonstra que a análise dos exames laboratoriais permite a detecção inicial dos problemas de toxicidade induzida pela quimioterapia, possibilitando o ajuste de dose antes do agravamento da toxicidade, que poderia levar a interrupção do tratamento (BROK et al, 2017;ROYER-PAKORA, 2018;YING et al, 2019;SPREAFICO, 2016). As principais recomendações encontram-se descritas na Figura 2.…”