Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity

Cinzia Giordano, Francesca Chemi, Salvatore Panza, Ines Barone, Daniela Bonofiglio, Marilena Lanzino, Angela Cordella, Antonella Campana, Adnan Hashim, Pietro Rizza, Antonella Leggio, Balázs Gyorffy, Bruno M. Simões, Robert B. Clarke, Alessandro Weisz, Stefania Catalano, Sebastiano Andò

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and therapeutic resistance. A strict dependency between BCSCs and stromal cell components of tumor microenvironment exists. Thus, novel therapeutic strategies aimed to target the crosstalk between activated microenvironment and BCSCs have the potential to improve clinical outcome. Here, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using patientderived samples (n = 16) and breast cancer cell lines, and determined the potential benefit of targeting leptin signaling in these model systems. Conditioned media (CM) from cancer-associated fibroblasts and breast adipocytes significantly increased mammosphere formation in breast cancer cells and depletion of leptin from CM completely abrogated this effect. Mammosphere cultures exhibited increased leptin receptor (OBR) expression and leptin exposure enhanced mammosphere formation. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology among mammospheres treated with CM and leptin. Interestingly, leptin increased mammosphere formation in metastatic breast cancers and expression of OBR as well as HSP90, a target of leptin signaling, were directly correlated with mammosphere formation in metastatic samples (r = 0.68/p = 0.05; r = 0.71/p = 0.036, respectively). Kaplan-Meier survival curves indicated that OBR and HSP90 expression were associated with reduced overall survival in breast cancer patients (HR = 1.9/p = 0.022; HR = 2.2/p = 0.00017, respectively). Furthermore, blocking leptin signaling by using a full leptin receptor antagonist significantly reduced mammosphere formation in breast cancer cell lines and patient-derived samples. Our results suggest that leptin/leptin receptor signaling may represent a potential therapeutic target that can block the stromal-tumor interactions driving BCSCmediated disease progression.

Original languageEnglish
Pages (from-to)1262-1275
Number of pages14
JournalOncotarget
Volume7
Issue number2
DOIs
Publication statusPublished - 2016

Fingerprint

Neoplastic Stem Cells
Leptin
Breast Neoplasms
Leptin Receptors
Neoplasms
Conditioned Culture Medium
Cell Line
Tumor Microenvironment
Kaplan-Meier Estimate
Cellular Structures
Microarray Analysis
Stromal Cells
Transcriptome
Adipocytes
Cell Biology
Disease Progression
Breast
Stem Cells
Therapeutics
Neoplasm Metastasis

Keywords

  • Breast cancer
  • Breast cancer stem cells
  • CAFs
  • Leptin
  • Microenvironment

ASJC Scopus subject areas

  • Oncology

Cite this

Giordano, C., Chemi, F., Panza, S., Barone, I., Bonofiglio, D., Lanzino, M., ... Andò, S. (2016). Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity. Oncotarget, 7(2), 1262-1275. https://doi.org/10.18632/oncotarget.6014

Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity. / Giordano, Cinzia; Chemi, Francesca; Panza, Salvatore; Barone, Ines; Bonofiglio, Daniela; Lanzino, Marilena; Cordella, Angela; Campana, Antonella; Hashim, Adnan; Rizza, Pietro; Leggio, Antonella; Gyorffy, Balázs; Simões, Bruno M.; Clarke, Robert B.; Weisz, Alessandro; Catalano, Stefania; Andò, Sebastiano.

In: Oncotarget, Vol. 7, No. 2, 2016, p. 1262-1275.

Research output: Contribution to journalArticle

Giordano, C, Chemi, F, Panza, S, Barone, I, Bonofiglio, D, Lanzino, M, Cordella, A, Campana, A, Hashim, A, Rizza, P, Leggio, A, Gyorffy, B, Simões, BM, Clarke, RB, Weisz, A, Catalano, S & Andò, S 2016, 'Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity', Oncotarget, vol. 7, no. 2, pp. 1262-1275. https://doi.org/10.18632/oncotarget.6014
Giordano C, Chemi F, Panza S, Barone I, Bonofiglio D, Lanzino M et al. Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity. Oncotarget. 2016;7(2):1262-1275. https://doi.org/10.18632/oncotarget.6014
Giordano, Cinzia ; Chemi, Francesca ; Panza, Salvatore ; Barone, Ines ; Bonofiglio, Daniela ; Lanzino, Marilena ; Cordella, Angela ; Campana, Antonella ; Hashim, Adnan ; Rizza, Pietro ; Leggio, Antonella ; Gyorffy, Balázs ; Simões, Bruno M. ; Clarke, Robert B. ; Weisz, Alessandro ; Catalano, Stefania ; Andò, Sebastiano. / Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity. In: Oncotarget. 2016 ; Vol. 7, No. 2. pp. 1262-1275.
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