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

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 patient-derived 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 BCSC-mediated disease progression.

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…Serum from obese patients increased a breast cancer stem cell population by 30% compared with 7% for lean control serum [103]. In breast cancer cell lines, silencing the leptin receptor may reduce cancer stem cell-like properties and EMT transition [104], and treatment of breast cancer cells with leptin from tumour stroma induced stem-like properties [105]. In cell line models of breast cancer, leptin appeared to activate the proinflammatory STAT3 pathway, recruiting G9a and causing repression of miR-200c via epigenetic silencing to induce the EMT stem cell phenotype [106].…”

Targeting cancer stem cell pathways for cancer therapy

“…486 Fibroblast-derived CCL-2 regulates CSCs through gap activation, thus promoting the progression of tumors. 487 CAFs and adipocytes also secrete leptin, which increases the globulation rate of breast CSCs in vitro. 488 CAFs also regulate the proliferation of CSCs by other signaling pathways.…”

Leptin signaling and cancer chemoresistance: Perspectives

“…Moreover, latest reports show a positive correlation between leptin, Ob-R and Notch components in endometrial cancer tissues from obese patients[70]. Leptin induces RBP-Jk and Notch that impacts on CSC and self-renewal[16,60,71]. Moreover, a novel crosstalk between Notch, IL-1 and leptin (NILCO) was found in breast cancer[53,60,72].…”