TY - JOUR
T1 - Hematopoietic age at onset of triple-negative breast cancer dictates disease aggressiveness and progression
AU - Marsh, Timothy
AU - Wong, Irene
AU - Sceneay, Jaclyn
AU - Barakat, Amey
AU - Qin, Yuanbo
AU - Sjodin, Andreas
AU - Alspach, Elise
AU - Nilsson, Bjorn
AU - Stewart, Sheila A.
AU - Mcallister, Sandra S.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/5/15
Y1 - 2016/5/15
N2 - Triple-negative breast cancer (TNBC) is considered an early onset subtype of breast cancer that carries with it a poorer prognosis in young rather than older women for reasons that remain poorly understood. Hematopoiesis in the bone marrow becomes altered with age and may therefore affect the composition of tumor-infiltrating hematopoietic cells and subsequent tumor progression. In this study, we investigated how age- and tumor-dependent changes to bone marrow-derived hematopoietic cells impact TNBC progression. Using multiple mouse models of TNBC tumorigenesis and metastasis, we found that a specific population of bone marrow cells (BMC) upregulated CSF-1R and secreted the growth factor granulin to support stromal activation and robust tumor growth in young mice. However, the same cell population in old mice expressed low levels of CSF1R and granulin and failed to promote tumor outgrowth, suggesting that age influences the tumorigenic capacity of BMCs in response to tumor-associated signals. Importantly, BMCs from young mice were sufficient to activate a tumor-supportive microenvironment and induce tumor progression in old mice. These results indicate that hematopoietic age is an important determinant of TNBC aggressiveness and provide rationale for investigating age-stratified therapies designed to prevent the protumorigenic effects of activated BMCs.
AB - Triple-negative breast cancer (TNBC) is considered an early onset subtype of breast cancer that carries with it a poorer prognosis in young rather than older women for reasons that remain poorly understood. Hematopoiesis in the bone marrow becomes altered with age and may therefore affect the composition of tumor-infiltrating hematopoietic cells and subsequent tumor progression. In this study, we investigated how age- and tumor-dependent changes to bone marrow-derived hematopoietic cells impact TNBC progression. Using multiple mouse models of TNBC tumorigenesis and metastasis, we found that a specific population of bone marrow cells (BMC) upregulated CSF-1R and secreted the growth factor granulin to support stromal activation and robust tumor growth in young mice. However, the same cell population in old mice expressed low levels of CSF1R and granulin and failed to promote tumor outgrowth, suggesting that age influences the tumorigenic capacity of BMCs in response to tumor-associated signals. Importantly, BMCs from young mice were sufficient to activate a tumor-supportive microenvironment and induce tumor progression in old mice. These results indicate that hematopoietic age is an important determinant of TNBC aggressiveness and provide rationale for investigating age-stratified therapies designed to prevent the protumorigenic effects of activated BMCs.
UR - http://www.scopus.com/inward/record.url?scp=84971528846&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-3332
DO - 10.1158/0008-5472.CAN-15-3332
M3 - Article
C2 - 27197230
AN - SCOPUS:84971528846
VL - 76
SP - 2932
EP - 2943
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 10
ER -