To the editor:
Notta et al elegantly demonstrated that engraftment of human hematopoietic stem cells (HSCs) is more efficient in female NOD/SCID/IL-2Rgcnull (NSG) recipients.1 Considering that NSG mice are now widely used to study HSCs and cancer stem cells (CSCs) from different types of cancer,2-4 this finding has profound potential biologic and clinical implications.
Along a similar way, we have recently observed a significant difference in tumor growth between male and female NSG mice injected orthotopically with 6 different hepatocellular carcinoma (HCC) cells derived from either male or female human patients. Approval for these studies was obtained from the institutional review boards of the participating institutions. Cancer cell lines were derived from human pateints who gave informed consent in accordance with the Declaration of Helsinki. In this model, the tumor growth was significantly larger and faster in male recipients (Figure 1).
Male NOD/SCID/IL-2Rgnull mice more efficiently support human HCC progression than syngeneic female mice. (Top panels) HCC tumors grow faster and have a higher volume in male than female NSG recipients. PLC/PRF-5 and SNU-387 derived from female patients and HepG2, HUH7, SNU-475, and a primary HCC derived from male patients (105 cells/20μL) were injected orthotopically in the subsera of the liver of 8-week-old male and female NSG mice. (A) HUH7 tumor growth was monitored by weekly detection of human α-fetoprotein (AFP) secreted specifically by tumor cells in the plasma by a chemoluminescent particles immunoassay (CMIA) and analyzed in an ARCHITECT optical system (Abbott Laboratories). Results are mean ± SD (female n = 10, males n = 15). (B) Human AFP levels at sacrifice reveals that hepatic tumors are larger in all HCC cells lines tested and in a primary HCC culture. SNU-387 and SNU-475 were found to be not tumorigenic in this animal model. (Bottom panels) Ventral views of the orthotopic TGL-HUH7 tumor model. Tumor progression was followed using the IVIS Imaging System (Xenogen) weekly. A strong statistical association between mean bioluminescence and plasma AFP (in mg/mL) was found (R2 = 0.914).
Male NOD/SCID/IL-2Rgnull mice more efficiently support human HCC progression than syngeneic female mice. (Top panels) HCC tumors grow faster and have a higher volume in male than female NSG recipients. PLC/PRF-5 and SNU-387 derived from female patients and HepG2, HUH7, SNU-475, and a primary HCC derived from male patients (105 cells/20μL) were injected orthotopically in the subsera of the liver of 8-week-old male and female NSG mice. (A) HUH7 tumor growth was monitored by weekly detection of human α-fetoprotein (AFP) secreted specifically by tumor cells in the plasma by a chemoluminescent particles immunoassay (CMIA) and analyzed in an ARCHITECT optical system (Abbott Laboratories). Results are mean ± SD (female n = 10, males n = 15). (B) Human AFP levels at sacrifice reveals that hepatic tumors are larger in all HCC cells lines tested and in a primary HCC culture. SNU-387 and SNU-475 were found to be not tumorigenic in this animal model. (Bottom panels) Ventral views of the orthotopic TGL-HUH7 tumor model. Tumor progression was followed using the IVIS Imaging System (Xenogen) weekly. A strong statistical association between mean bioluminescence and plasma AFP (in mg/mL) was found (R2 = 0.914).
Taken together, these data and Notta et al's data underline the need for using a selected sex of the mice in quantitative HSC and CSC studies using NSG mice.
Authorship
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Francesco Bertolini, IEO, Via Ripamonti 435, Milan, MI 20141, Italy; e-mail: francesco.bertolini@ieo.it.
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