Abstract
The explanation for cancer recurrence still remains to be fully elucidated. Moreover, tumor dormancy, which is a process whereby cells enter reversible G0 cell cycle arrest, appears to be a critical step in this phenomenon. We evaluated the cell cycle proliferation pattern in pediatric tumor-derived mesenchymal stromal cells (MSCs), in order to provide a better understanding of the complex mechanisms underlying cancer dormancy. Specimens were obtained from 14 pediatric patients diagnosed with solid tumors and submitted to surgery. Morphology, phenotype, differentiation, immunological capacity, and proliferative growth of tumor MSCs were studied. Flow cytometric analysis was performed to evaluate the cell percentage of each cell cycle phase. Healthy donor bone marrow-derived mesenchymal stromal cells (BM-MSCs) were employed as controls. It was noted that the DNA profile of proliferating BM-MSC was different from that of tumor MSCs. All BM-MSCs expressed the typical DNA profile of proliferating cells, while in all tumor MSC samples, ≥70% of the cells were detected in the G0/G1 phase. In particular, seven tumor MSC samples displayed intermediate cell cycle behavior, and the other seven tumor MSC samples exhibited a slow cell cycle. The increased number of tumor MSCs in the G0–G1 phase compared with BM-MSCs supports a role for quiescent MSCs in tumor dormancy regulation. Understanding the mechanisms that promote dormant cell cycle arrest is essential in identifying predictive markers of recurrence and to promote a dedicated surgical planning.
Highlights
The overall incidence rates of childhood cancer vary between 50 and 200 per million children across the world [1]
A proposed mechanism underlying the persistence of covert cancer cells during and after treatment is that some cancer stem cells enter a reversible quiescent or dormant state in which they are relatively resistant to radiation and chemotherapy
The aim of this study was to characterize the proliferation pattern of the cell cycle in pediatric tumor-derived mesenchymal stromal cells (MSCs), in order to enhance our understanding of the complex mechanisms, implicated in the cancer dormancy process, that may influence therapeutic response
Summary
The overall incidence rates of childhood cancer vary between 50 and 200 per million children across the world [1]. Conventional chemotherapy regimens include DNA-damaging agents and spindle poisons, and their effect is, dependent on the active cycling of tumoral cells through the S and M cell cycle phases, respectively. Both cell intrinsic characteristics and extrinsic influences from surrounding normal cells determine tumor cell dormancy [7]. Mesenchymal stromal cells play different roles in modulating tumor progression, growth, and metastasis. It has been reported that a paracrine effect of cancer cells slows cycling and chemoresistance, through the secretion of soluble factors promoting a more stem-like state of MSCs [10]. The contact between cancer cells and MSCs in regulating cancer dormancy should not be excluded [11]
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