CLL exosomes promote stromal cell transition into cancer-associated fibroblasts


Exosomes released by chronic lymphocytic leukemia (CLL) cells induce stromal cells to adopt a cancer-associated fibroblast phenotype, thereby creating a microenvironment conducive to CLL cell adhesion, survival, and growth.

Although the role of exosomes in other cancers has been well studied, their role in hematologic malignancies has not been well characterized. Also, this study confirmed that exosomes are present in CLL lymph nodes and promote tumor growth in vivo.

“Our in vitro and in vivo data show that CLL exosomes harbor an oncogenic potential by stimulating stromal cells to induce an inflammatory and protumorigenic milieu, including increased angiogenesis, thus supporting the survival and outgrowth of CLL cells,” wrote Jerome Paggetti, Ph.D., of the laboratory of experimental hemato-oncology, Luxembourg Institute of Health (Blood 2015 Aug 27. doi: 10.1182/blood-2014-12-618025 ).

Cells were obtained from 21 CLL patients; all patients had an absolute lymphocyte count of more than 30,000/mcL and were untreated for 3 months. The researchers established 30-day cocultures of bone marrow mesenchymal stem cells with primary CLL cells in culture inserts or they treated bone marrow mesenchymal stem cells weekly with exosomes. Similar experiments were performed with the Burkitt lymphoma cell line Namalwa to investigate whether the impact on stromal cells is CLL specific.

Based on gene expression analysis, CLL exosomes and CLL cells cocultured in inserts induced similar gene expression changes in bone marrow mesenchymal stem cells, highlighting the relevance of exosomes for microenvironment changes. “Importantly, lymphoma cells induced a distinct gene expression pattern in bone marrow mesenchymal stem cells, suggesting a specific response to CLL exosomes,” wrote Dr. Paggetti and coauthors.

The impact of CLL exosomes on tumor growth was studied in vivo by subcutaneously injecting cells with and without CLL exosomes into immunocompromised mice. Cells supplemented with exosomes resulted in an increased tumor size compared with tumor cells injected without additional exosomes. Also, the cells supplemented with exosomes accumulated in mice kidneys, confirming the renal involvement observed in CLL patients. “Our data demonstrate a protumorigenic effect of CLL-derived exosomes in vivo and their importance in the early onset of the disease when tumor cells impact the microenvironment to proliferate and promote angiogenesis,” the researchers concluded.


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