In vitro and in vivo antiproliferative activity of metformin on stem-like cells isolated from spontaneous canine mammary carcinomas: Translational implications for human tumors

Federica Barbieri, Stefano Thellung, Alessandra Ratto, Elisa Carra, Valeria Marini, Carmen Fucile, Adriana Bajetto, Alessandra Pattarozzi, Roberto Würth, Monica Gatti, Chiara Campanella, Guendalina Vito, Francesca Mattioli, Aldo Pagano, Antonio Daga, Angelo Ferrari, Tullio Florio

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: Cancer stem cells (CSCs) are considered the cell subpopulation responsible for breast cancer (BC) initiation, growth, and relapse. CSCs are identified as self-renewing and tumor-initiating cells, conferring resistance to chemo- and radio-therapy to several neoplasias. Nowadays, th (about 10mM)e pharmacological targeting of CSCs is considered an ineludible therapeutic goal. The antidiabetic drug metformin was reported to suppress in vitro and in vivo CSC survival in different tumors and, in particular, in BC preclinical models. However, few studies are available on primary CSC cultures derived from human postsurgical BC samples, likely because of the limited amount of tissue available after surgery. In this context, comparative oncology is acquiring a relevant role in cancer research, allowing the analysis of larger samples from spontaneous pet tumors that represent optimal models for human cancer. Methods: Isolation of primary canine mammary carcinoma (CMC) cells and enrichment in stem-like cell was carried out from fresh tumor specimens by culturing cells in stem-permissive conditions. Phenotypic and functional characterization of CMC-derived stem cells was performed in vitro, by assessment of self-renewal, long-lasting proliferation, marker expression, and drug sensitivity, and in vivo, by tumorigenicity experiments. Corresponding cultures of differentiated CMC cells were used as internal reference. Metformin efficacy on CMC stem cell viability was analyzed both in vitro and in vivo. Results: We identified a subpopulation of CMC cells showing human breast CSC features, including expression of specific markers (i.e. CD44, CXCR4), growth as mammospheres, and tumor-initiation in mice. These cells show resistance to doxorubicin but were highly sensitive to metformin in vitro. Finally, in vivo metformin administration significantly impaired CMC growth in NOD-SCID mice, associated with a significant depletion of CSCs. Conclusions: Similarly to the human counterpart, CMCs contain stem-like subpopulations representing, in a comparative oncology context, a valuable translational model for human BC, and, in particular, to predict the efficacy of antitumor drugs. Moreover, metformin represents a potential CSC-selective drug for BC, as effective (neo-)adjuvant therapy to eradicate CSC in mammary carcinomas of humans and animals.

Original languageEnglish
Article number228
JournalBMC Cancer
Volume15
Issue number1
DOIs
Publication statusPublished - Apr 7 2015

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Metformin
Neoplastic Stem Cells
Canidae
Stem Cells
Breast Neoplasms
Neoplasms
In Vitro Techniques
Cell Survival
Animal Mammary Neoplasms
Growth
Inbred NOD Mouse
SCID Mice
Pets
Therapeutics
Radio
Hypoglycemic Agents
Pharmaceutical Preparations
Antineoplastic Agents
Doxorubicin
Cell Culture Techniques

Keywords

  • Breast cancer
  • Cancer stem cells
  • Comparative oncology
  • Metformin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

In vitro and in vivo antiproliferative activity of metformin on stem-like cells isolated from spontaneous canine mammary carcinomas : Translational implications for human tumors. / Barbieri, Federica; Thellung, Stefano; Ratto, Alessandra; Carra, Elisa; Marini, Valeria; Fucile, Carmen; Bajetto, Adriana; Pattarozzi, Alessandra; Würth, Roberto; Gatti, Monica; Campanella, Chiara; Vito, Guendalina; Mattioli, Francesca; Pagano, Aldo; Daga, Antonio; Ferrari, Angelo; Florio, Tullio.

In: BMC Cancer, Vol. 15, No. 1, 228, 07.04.2015.

Research output: Contribution to journalArticle

Barbieri, F, Thellung, S, Ratto, A, Carra, E, Marini, V, Fucile, C, Bajetto, A, Pattarozzi, A, Würth, R, Gatti, M, Campanella, C, Vito, G, Mattioli, F, Pagano, A, Daga, A, Ferrari, A & Florio, T 2015, 'In vitro and in vivo antiproliferative activity of metformin on stem-like cells isolated from spontaneous canine mammary carcinomas: Translational implications for human tumors', BMC Cancer, vol. 15, no. 1, 228. https://doi.org/10.1186/s12885-015-1235-8
Barbieri, Federica ; Thellung, Stefano ; Ratto, Alessandra ; Carra, Elisa ; Marini, Valeria ; Fucile, Carmen ; Bajetto, Adriana ; Pattarozzi, Alessandra ; Würth, Roberto ; Gatti, Monica ; Campanella, Chiara ; Vito, Guendalina ; Mattioli, Francesca ; Pagano, Aldo ; Daga, Antonio ; Ferrari, Angelo ; Florio, Tullio. / In vitro and in vivo antiproliferative activity of metformin on stem-like cells isolated from spontaneous canine mammary carcinomas : Translational implications for human tumors. In: BMC Cancer. 2015 ; Vol. 15, No. 1.
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T1 - In vitro and in vivo antiproliferative activity of metformin on stem-like cells isolated from spontaneous canine mammary carcinomas

T2 - Translational implications for human tumors

AU - Barbieri, Federica

AU - Thellung, Stefano

AU - Ratto, Alessandra

AU - Carra, Elisa

AU - Marini, Valeria

AU - Fucile, Carmen

AU - Bajetto, Adriana

AU - Pattarozzi, Alessandra

AU - Würth, Roberto

AU - Gatti, Monica

AU - Campanella, Chiara

AU - Vito, Guendalina

AU - Mattioli, Francesca

AU - Pagano, Aldo

AU - Daga, Antonio

AU - Ferrari, Angelo

AU - Florio, Tullio

PY - 2015/4/7

Y1 - 2015/4/7

N2 - Background: Cancer stem cells (CSCs) are considered the cell subpopulation responsible for breast cancer (BC) initiation, growth, and relapse. CSCs are identified as self-renewing and tumor-initiating cells, conferring resistance to chemo- and radio-therapy to several neoplasias. Nowadays, th (about 10mM)e pharmacological targeting of CSCs is considered an ineludible therapeutic goal. The antidiabetic drug metformin was reported to suppress in vitro and in vivo CSC survival in different tumors and, in particular, in BC preclinical models. However, few studies are available on primary CSC cultures derived from human postsurgical BC samples, likely because of the limited amount of tissue available after surgery. In this context, comparative oncology is acquiring a relevant role in cancer research, allowing the analysis of larger samples from spontaneous pet tumors that represent optimal models for human cancer. Methods: Isolation of primary canine mammary carcinoma (CMC) cells and enrichment in stem-like cell was carried out from fresh tumor specimens by culturing cells in stem-permissive conditions. Phenotypic and functional characterization of CMC-derived stem cells was performed in vitro, by assessment of self-renewal, long-lasting proliferation, marker expression, and drug sensitivity, and in vivo, by tumorigenicity experiments. Corresponding cultures of differentiated CMC cells were used as internal reference. Metformin efficacy on CMC stem cell viability was analyzed both in vitro and in vivo. Results: We identified a subpopulation of CMC cells showing human breast CSC features, including expression of specific markers (i.e. CD44, CXCR4), growth as mammospheres, and tumor-initiation in mice. These cells show resistance to doxorubicin but were highly sensitive to metformin in vitro. Finally, in vivo metformin administration significantly impaired CMC growth in NOD-SCID mice, associated with a significant depletion of CSCs. Conclusions: Similarly to the human counterpart, CMCs contain stem-like subpopulations representing, in a comparative oncology context, a valuable translational model for human BC, and, in particular, to predict the efficacy of antitumor drugs. Moreover, metformin represents a potential CSC-selective drug for BC, as effective (neo-)adjuvant therapy to eradicate CSC in mammary carcinomas of humans and animals.

AB - Background: Cancer stem cells (CSCs) are considered the cell subpopulation responsible for breast cancer (BC) initiation, growth, and relapse. CSCs are identified as self-renewing and tumor-initiating cells, conferring resistance to chemo- and radio-therapy to several neoplasias. Nowadays, th (about 10mM)e pharmacological targeting of CSCs is considered an ineludible therapeutic goal. The antidiabetic drug metformin was reported to suppress in vitro and in vivo CSC survival in different tumors and, in particular, in BC preclinical models. However, few studies are available on primary CSC cultures derived from human postsurgical BC samples, likely because of the limited amount of tissue available after surgery. In this context, comparative oncology is acquiring a relevant role in cancer research, allowing the analysis of larger samples from spontaneous pet tumors that represent optimal models for human cancer. Methods: Isolation of primary canine mammary carcinoma (CMC) cells and enrichment in stem-like cell was carried out from fresh tumor specimens by culturing cells in stem-permissive conditions. Phenotypic and functional characterization of CMC-derived stem cells was performed in vitro, by assessment of self-renewal, long-lasting proliferation, marker expression, and drug sensitivity, and in vivo, by tumorigenicity experiments. Corresponding cultures of differentiated CMC cells were used as internal reference. Metformin efficacy on CMC stem cell viability was analyzed both in vitro and in vivo. Results: We identified a subpopulation of CMC cells showing human breast CSC features, including expression of specific markers (i.e. CD44, CXCR4), growth as mammospheres, and tumor-initiation in mice. These cells show resistance to doxorubicin but were highly sensitive to metformin in vitro. Finally, in vivo metformin administration significantly impaired CMC growth in NOD-SCID mice, associated with a significant depletion of CSCs. Conclusions: Similarly to the human counterpart, CMCs contain stem-like subpopulations representing, in a comparative oncology context, a valuable translational model for human BC, and, in particular, to predict the efficacy of antitumor drugs. Moreover, metformin represents a potential CSC-selective drug for BC, as effective (neo-)adjuvant therapy to eradicate CSC in mammary carcinomas of humans and animals.

KW - Breast cancer

KW - Cancer stem cells

KW - Comparative oncology

KW - Metformin

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