Neuroblastoma (NBL) is the most common extracranial solid cancer in children and with the steady increase of chemotherapeutic drug-resistance this tumor type represents a growing problem for clinicians and cancer researchers.
However, scientists at the Children’s Hospital Los Angeles (CHLA) have just uncovered what they believe is a critical pathway that allows drug-resistant NBL to persist and could open up new targets for therapeutic intervention.
The CHLA researchers looked into how exosomic microRNA (miRNA) released within the tumor microenvironment affects resistance to chemotherapy. Exosomes are small vesicles typically between 30 and 100 nanometers in diameter and have specialized cargo and functions ranging from cell waste management to cell signaling—they have become increasingly important over the past several years as potential biomarkers for various cancers.
“The main reason for the recurrence of neuroblastoma—and essentially, all types of cancer—is a growing resistance to treatments such as chemotherapy,” explained Muller Fabbri, M.D., Ph.D., assistant professor of microbiology, immunology, and pediatrics at The Saban Research Institute within CHLA. “The goal of this study was to assess whether, and to what extent, exosomic miRNAs are involved in the development of drug resistance through the tumor microenvironment.”
The findings from this study were published recently in the Journal of the National Center Institute “Exosome-Mediated Transfer of microRNAs Within the Tumor Microenvironment and Neuroblastoma Resistance to Chemotherapy.”
The tumor microenvironment is a veritable cross-talk channel where exosomes shuttle signaling molecules between NBL and various other cells of the immune system that are nearby. One such cell type that’s in close proximity are tumor-associated macrophages (TAMs). For NBL, TAMs represent a negative prognostic factor and Dr. Fabbri and his colleagues looked to determine if the macrophages were affecting drug resistance through the exchange of exosomic miRNA’s.
Interestingly, what the researchers found was that a specific miRNA called miR155, which has been shown previously to be upregulated in various cancers, was secreted into the microenvironment within exosomes and then picked up by NBL cells. Once inside the NBL cells, the researchers found that miR155 silences a gene named TERF-1, which functions as an inhibitor of telomerase.
Telomerase activity within normal cells helps to measure a cell’s age, signaling when time has come for the cell to die. High telomerase activity is a hallmark of cancer, and TERF1 protein levels are low in cancer cells that are resistant to chemotherapy—a scenario that Dr. Fabbri simply explains as “The cancer cells continue to live, even when they are supposed to die.”
The CHLA team took their findings a step further to determine if an inhibitor of exosomes would restore the drug-sensitive phenotype of NBL cells—in essence blocking the mail delivery system. Through an array of in vitro and in vivo assays their hypothesis was confirmed, as more cancer cells died in the presence of the exosome inhibitor when compared to the controls.
“By discovering this complicated molecular mechanism behind how the presence of TAMs works to worsen the prognosis of a patient with neuroblastoma, we now know what to target,” concluded Dr. Fabbri.