Concise Review: An (Im)Penetrable Shield: How the Tumor Microenvironment Protects Cancer Stem Cells

Abstract

Cancer stem cells (CSCs) are defined by their unlimited self-renewal ability and their capacity to initiate and maintain malignancy, traits that are not found in most cells that comprise the tumor. Although current cancer treatments successfully reduce tumor burden, the tumor will likely recur unless CSCs are effectively eradicated. This challenge is made greater by the protective impact of the tumor microenvironment (TME), consisting of infiltrating immune cells, endothelial cells, extracellular matrix, and signaling molecules. The TME acts as a therapeutic barrier through immunosuppressive, and thereby tumor-promoting, actions. These factors, outside of the cancer cell lineage, work in concert to shelter CSCs from both the body's intrinsic anticancer immunity and pharmaceutical interventions to maintain cancer growth. Emerging therapies aimed at the TME offer a promising new tool in breaking through this shield to target the CSCs, yet definitive treatments remain unrealized. In this review, we summarize the mechanisms by which CSCs are protected by the TME and current efforts to overcome these barriers. STEM CELLS 2017;35:1123-1130 SIGNIFICANCE STATEMENTCancer stem cells differ from bulk tumor cells due to their ability to create a heterogeneous tumor population, unlimited self-renewal, and proliferation. The tumor microenvironment (TME) provides a shelter for these cells through the presence and actions of stroma, vasculature, extracellular matrix, signaling molecules, and immune cells. The TME has increasingly been recognized as an important component of therapy resistance and tumor progression. Unlike tumor cells, the critical components that comprise the TME and their roles in tumor progression are common between different cancers. A thorough understanding of cancer stem cell-TME interactions is vital to the development of innovative therapeutics.

Intratumoral Delivery of Interferonγ-Secreting Mesenchymal Stromal Cells Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo

“…The TME remains one of the largest challenges to successful cancer therapies. Through physical and chemical barriers to therapy penetrance, including a dense extracellular matrix, tortuous vasculature, aberrant metabolism, and immune suppression, tumors are able to evade detection and immune‐mediated killing . Altering the TME to facilitate drug delivery and impact represents a major goal in oncology.…”

“…Effectively killing cancer cells is complicated by multiple factors within the TME . For example, cancer cells secrete a dense matrix which physically impedes the body's immune cells or drugs from accessing the cancer cells.…”

Tumor Microenvironment

“…Controlling the proliferation of cancer stem cells is not easy, and this challenge is made more difficult by the protective effect of the TME, which consists of infiltrating endothelial cells, immune cells, signaling molecules, and ECM [65]. The TME tends to act as a therapeutic barrier that promotes tumor development and progression due to its immunosuppressive capabilities [64].…”

Lung cancer stem cells—origin, characteristics and therapy

“…The cancer microenvironment is constituted of a thicker ECM than that found in the normal one. Tumor microenvironments holding different factors can also indirectly facilitate the tumor heterogeneity and resistance to chemotherapy (28,29).…”