First name
Francesca
Last name
Reggiani
Year of Study
Research Center
Thesis Title
GM-CSF and MMP9 are key regulators of the effect of adipose progenitors over breast cancer onset and metastatic progression
Thesis Abstract
Recent epidemiological and clinical data underlined the critical role of obesity in breast cancer (BC) progression. A population with progenitor-like phenotype (CD45-CD34+) was detected in white adipose tissue (WAT) and was reported to support local and metastatic BC. This population is composed by distinct WAT progenitors: adipose-derived stem cells (ASCs) and endothelial progenitor cells (EPCs), displaying complementary role in BC progression. The molecular mechanisms involved in this interaction need to be clarified.
Two proteins were significantly up-regulated in WAT-derived progenitors after being co-cultured with several BC cells: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and Matrix metallopeptidase 9 (MMP9). Both factors were detected over-expressed in xenograft models, when co-injected with BC and human WAT progenitors. ASC and EPCs displayed similar ability to induce GM-CSF/MMP9, suggesting a complementary role in their release. The neutralization of GM-CSF in diet-induced obese (DIO) syngeneic mice led to reduced intratumor vascularization and strong impairment of immunosuppressive microenvironment. This resulted in a significant impairment of local BC growth and a slower metastatic progression. Conversely, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth.
Metformin was reported to significantly affect tumor progression and neoplastic angiogenesis, targeting both BC and WAT cells. In the present study, Metformin inhibited GM-CSF and MMP9 release from WAT progenitors in vitro and in xenograft models.
Collectively, these results indicate GM-CSF and MMP9 as new potential targets to prevent the pro-tumorigenic effect of WAT progenitors on BC. Furthermore, Metformin ability to reduce GM-CSF and MMP9 supports Metformin administration in clinical studies.
Two proteins were significantly up-regulated in WAT-derived progenitors after being co-cultured with several BC cells: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and Matrix metallopeptidase 9 (MMP9). Both factors were detected over-expressed in xenograft models, when co-injected with BC and human WAT progenitors. ASC and EPCs displayed similar ability to induce GM-CSF/MMP9, suggesting a complementary role in their release. The neutralization of GM-CSF in diet-induced obese (DIO) syngeneic mice led to reduced intratumor vascularization and strong impairment of immunosuppressive microenvironment. This resulted in a significant impairment of local BC growth and a slower metastatic progression. Conversely, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth.
Metformin was reported to significantly affect tumor progression and neoplastic angiogenesis, targeting both BC and WAT cells. In the present study, Metformin inhibited GM-CSF and MMP9 release from WAT progenitors in vitro and in xenograft models.
Collectively, these results indicate GM-CSF and MMP9 as new potential targets to prevent the pro-tumorigenic effect of WAT progenitors on BC. Furthermore, Metformin ability to reduce GM-CSF and MMP9 supports Metformin administration in clinical studies.
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