Growth factor receptor trafficking as a potential therapeutic target in pediatric cancer

Abstract

Growth factor receptors (GFRs) are often aberrantly expressed in tumor cells, and altered GFR expression and activity contribute to the pathogenesis of many types of cancer. A variety of mechanisms have been identified that result in enhanced GFR expression and activity in cancer cells. Defects in the pathways responsible for GFR internalization and intracellular trafficking are likely to be involved in altered GFR expression in a variety of cancers. The roles of GFR trafficking pathways in the regulation of GFR expression, in the pathogenesis of tumors, and in the response of tumors to treatment have not been fully delineated, but the likely contributions of GFR signaling to the development and progression of various malignancies suggest that therapies that modify GFR trafficking may be effective as anticancer treatments.The intracellular trafficking of GFRs is regulated by a number of protein complexes and by protein ubiquitination. Many of the proteins required for this trafficking are products of tumor suppressor genes, and the expression and function of the protein machinery utilized for intracellular trafficking is frequently altered in tumor cells, consistent with the likely role of GFR trafficking in tumorigenesis. Many of the proteins involved in GFR trafficking have been identified as potential targets for anticancer treatment, and novel treatments directed against these targets are currently in preclinical development and in clinical trials. Ubiquitin ligases are critical for GFR trafficking and represent potentially important targets for the development of novel therapies.The genes for the ubiquitin ligases c-Cbl and UBE4B are located in chromosome regions commonly altered in a variety of tumors and therefore are likely to be important for tumorigenesis. c-Cbl ubiquitinates a number of GFRs and directs them for degradation. Mutations in c-Cbl have been identified in cases of myeloid leukemia and myelodysplasia, providing a link between GFR ubiquitination and trafficking and leukemogenesis. We have shown that UBE4B plays a crucial role in GFR trafficking and degradation in tumor cells, suggesting a previously uncharacterized link between UBE4B and tumorigenesis. With the critical need for new and effective therapies for pediatric malignancies, the recently identified roles for the GFR trafficking pathway in the pathogenesis of various forms of cancer confirm the importance of the further development of novel therapies targeting this pathway in children with cancer.

UBE4B levels are correlated with clinical outcomes in neuroblastoma patients and with altered neuroblastoma cell proliferation and sensitivity to epidermal growth factor receptor inhibitors

“…Aberrant GFR expression and function have been shown to be important in the pathogenesis of neuroblastoma. [25][26][27][28][29][30] We have observed that the UBE4B protein interacts with Hrs, a key regulator of EGFR endosomal trafficking and degradation, [31][32][33][34] and that the Hrs-UBE4B interaction is critical for efficient GFR trafficking and degradation, 14 suggesting that UBE4B expression and function may be associated with EGFR expression in neuroblastoma tumor cells. Therefore, we evaluated a cohort of 20 neuroblastoma tumor samples from the Children's Oncology Group (COG) for expression of UBE4B and EGFR proteins by quantitative Western blot analysis.…”

“…Deletions in the short arm of chromosome 1 (chromosome 1p36) are identified in approximately one‐third of neuroblastoma tumors and are associated with high‐risk tumor features and a poor prognosis 10‐12. The UBE4B gene is located in the 1p36 region and encodes an E3/E4 ubiquitin ligase 13, 14. Recently, Krona and colleagues identified a mutation in the UBE4B gene in the tumor from a patient with neuroblastoma with a fatal outcome 15.…”

“…We have observed that UBE4B interacts with hepatocyte growth factor‐regulated tyrosine kinase substrate (Hrs), a key regulator of the endosomal machinery for GFR trafficking, and that the UBE4B‐Hrs interaction is critical for appropriate GFR trafficking and degradation 14. Therefore, loss of UBE4B expression and function may be associated with aberrant GFR expression in neuroblastoma tumors.…”

“…[10][11][12] The UBE4B gene is located in the 1p36 region and encodes an E3/E4 ubiquitin ligase. 13,14 Recently, Krona and colleagues identified a mutation in the UBE4B gene in the tumor from a patient with neuroblastoma with a fatal outcome. 15 The expression of UBE4B was shown to be markedly diminished in a cohort of high-stage/poor-outcome tumors compared to low-stage/favorable-outcome tumors 15,16 , and UBE4B was therefore suggested to be a candidate tumor suppressor gene.…”

A Polymorphism in the FGFR4 Gene Is Associated With Risk of Neuroblastoma and Altered Receptor Degradation

“…Dysregulation of GFR trafficking is clearly emerging as an important mechanism for oncogenesis in a variety of human cancers. A large and growing body of evidence clearly demonstrates that disruption of the GFR trafficking pathways can alter cell expression and activity of GFRs, leading to the development and progression of cancer [38,39]. Therefore, developing a better understanding of the GFR trafficking pathways is critical in the understanding of the process of tumorigenesis.…”