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.
Highlights
Carcinoma of the breast is the most common malignancy and the leading cause of cancer-related death in women worldwide [1]
Our experiments demonstrated an increased self-renewal in MCF-7 cells treated with cancer-associated fibroblasts (CAFs)- and adipocyte-derived Conditioned media (CM) in the first generation compared with the untreated spheres (Figure 1B and 1C)
Given the role of leptin as an important cytokine secreted by both CAFs and adipocytes, we assessed the impact of leptin in the context of the heterotypic signaling working in Breast cancer stem cells (BCSCs)–stromal interactions
Summary
Carcinoma of the breast is the most common malignancy and the leading cause of cancer-related death in women worldwide [1]. Multiple reports have shown that a subpopulation of cancer cells displaying stem cell properties and named as cancer stem cells (CSCs) plays a crucial role in sustaining tumor growth and progression. These cells are characterized by their ability to undergo self-renewal, a process that drives tumorigenesis, and to differentiate into the non-self-renewing cells forming the tumor bulk [2, 3]. Strategies aimed to target the interaction between CSCs and their microenvironment may represent an important approach to improve patient outcome
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