Cancer Letters

Cancer Letters

Volume 421, 1 May 2018, Pages 17-27
Cancer Letters

Original Articles
Bone marrow-derived fibrocytes promote stem cell-like properties of lung cancer cells

https://doi.org/10.1016/j.canlet.2018.02.016Get rights and content

Highlights

  • The number of fibrocyte is correlated with a reduced OS of lung cancer patients.

  • Fibrocytes enhance the CSC-like properties of lung cancer through secreted factors.

  • The PIK3K/AKT pathway is critical for fibrocytes to mediate the CSC-like functions.

  • Targeting the AKT pathway may provide a therapeutic strategy against CSCs.

Abstract

Cancer stem cells (CSCs) represent a minor population that have clonal tumor initiation and self-renewal capacity and are responsible for tumor initiation, metastasis, and therapeutic resistance. CSCs reside in niches, which are composed of diverse types of stromal cells and extracellular matrix components. These stromal cells regulate CSC-like properties by providing secreted factors or by physical contact. Fibrocytes are differentiated from bone marrow-derived CD14+ monocytes and have features of both macrophages and fibroblasts. Accumulating evidence has suggested that stromal fibrocytes might promote cancer progression. However, the role of fibrocytes in the CSC niches has not been revealed. We herein report that human fibrocytes enhanced the CSC-like properties of lung cancer cells through secreted factors, including osteopontin, CC-chemokine ligand 18, and plasminogen activator inhibitor-1. The PIK3K/AKT pathway was critical for fibrocytes to mediate the CSC-like functions of lung cancer cells. In human lung cancer specimens, the number of tumor-infiltrated fibrocytes was correlated with high expression of CSC-associated protein in cancer cells. These results suggest that fibrocytes may be a novel cell population that regulates the CSC-like properties of lung cancer cells in the CSC niches.

Introduction

Tumor tissue is not a simple aggregate of homogenous cancer cells; rather, it is a complex cluster of various cell types, including not only cancer cells but also stromal cells [1]. Even among cancer cells, distinct phenotypic statuses that differ in functional attributes often exist, which makes it difficult to control their growth. In such a situation of tumor-cell heterogeneity, cancer stem cells (CSCs) represent a minor but important population that have been shown to have clonal tumor initiation and self-renewal capacity [2], and these stem cell-like properties are thought to be responsible for tumor metastasis, recurrence, and therapeutic resistance [3].

Thus far, various attempts have been made to target CSCs in order to regulate the progression of cancer; however, applicable treatment strategies have yet to be developed. This may be due in part to the fact that CSCs reside in and are protected by niches comprised of various stromal cells, providing desirable condition to CSCs by direct cell-cell contact or by secreted factors. In this regard, it is crucial to understand how these complex and specialized environments are formed, in order to control the fate of CSCs. Among the cells that comprise the CSC niche, cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) are reported to be important for maintaining the microenvironment [3]. However, given that the composition and mechanisms underlying the CSC niche have not been fully elucidated, we hypothesized that there are still as-yet-undiscovered cellular mechanisms underlying the composition of the CSC niche.

Fibrocytes are a minor population of leukocytes that differentiate from bone-marrow derived CD14+ monocytes. The distinctive feature of these cells is that they have fibroblast-like tissue remodeling properties in addition to their original inflammatory properties of macrophages [4]. We recently found that fibrocytes contribute to the acquired resistance to anti-VEGF therapy in lung cancer and malignant pleural mesothelioma by producing alternative angiogenic factors, such as FGF2 [5]. These results prompted us to consider that fibrocytes may also play a role in regulating cancer growth by affecting CSCs, as CSCs are deeply involved in drug resistance.

Under this hypothesis, we focused on fibrocytes as a previously unrecognized cell type involved in CSC niche.

Section snippets

Cell lines

The human lung adenocarcinoma cell line A549 was purchased from the American Type Culture Collection. The human small cell lung cancer cell line SBC-5 was kindly provided by Drs. M. Tanimoto and K. Kiura (Okayama University, Okayama, Japan). These cell lines were authenticated and maintained according to previously published methods [5,6].

Reagents

The anti-mouse IL-2 receptor β-chain monoclonal antibody TM-β1 was supplied by Drs. M. Miyasaka and T. Tanaka (Osaka University, Osaka, Japan). Cisplatin was

The accumulation of fibrocytes in human lung cancer tissue

Initially, to determine whether or not fibrocytes were involved in lung cancer progression in clinical settings, we carried out immunohistochemical studies with surgically resected samples from lung cancer patients. Fibrocytes in the tissue section are usually identified with the expression of a marker of fibroblasts such as collagen production together with the expression of CD34 and/or CD45 [4]. However, these approaches may include some population of fibroblasts and macrophages. Therefore,

Discussion

Fibrocytes are differentiated from bone-marrow derived monocytes and share the inflammatory features of macrophages and tissue remodeling properties of fibroblasts [21]. Based on their inflammatory and fibrogenic abilities, fibrocytes were previously reported to be involved in the pathogenesis of various fibrotic diseases, such as asthma and interstitial pulmonary fibrosis [4,22]. In the tumor microenvironment, however, only a few studies have reported their immunosuppressive role and

Conflicts of interest

The authors declare that we have no conflict of interest.

Acknowledgement

We thank Drs. M. Tanimoto and K. Kiura (Okayama University, Okayama, Japan) for providing the cell line and Dr. M. Miyasaka (Osaka University, Japan) for providing TM-β1. We also thank our colleagues at Tokushima University, especially T. Oka for her technical assistance with primary cell isolation, Megumi Kume and Yuuki Morimoto for their technical assistance with preparing and staining thin sections of patients, and the members of the Nishioka lab for their technical advice and fruitful

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