Breast Cancer: Current Research
Open Access

Tumor microenvironment; Cancer stem cells; Hypoxia; Immune evasion; Extracellular matrix; Stromal cells; Chemoresistance; Metastasis

Introduction

Cancer is a heterogeneous disease characterized by the presence of diverse cell populations within the tumor mass. Among these populations, cancer stem cells (CSCs) have gained attention due to their capacity for self-renewal, differentiation, and resistance to conventional therapies. The concept of CSCs proposes that only a small subset of cells within a tumor is responsible for sustaining tumor growth, metastasis, and recurrence. However, the behavior of CSCs is not solely intrinsic to their nature; it is profoundly influenced by the tumor microenvironment (TME), which provides essential cues that regulate CSC function [1,2].

The TME comprises a variety of components, including stromal cells, immune cells, blood vessels, extracellular matrix (ECM), and soluble factors such as cytokines and growth factors. This review aims to examine how different elements of the TME contribute to the regulation of CSCs and how these interactions impact cancer progression and resistance to treatment [3].

Components of the Tumor Microenvironment

Hypoxia: Hypoxia, or low oxygen levels, is a hallmark of solid tumors due to their rapid growth and insufficient blood supply. Hypoxia-inducible factors (HIFs) play a key role in the adaptation of cells to hypoxic conditions. In CSCs, HIFs up regulate genes associated with stemness, invasion, and resistance to apoptosis, enhancing their tumor-initiating capacity. Hypoxia has been shown to promote the expression of stem cell markers, such as OCT4, SOX2, and NANOG, which are crucial for maintaining CSC properties. Moreover, hypoxia increases the expression of genes involved in angiogenesis (e.g., VEGF) and epithelial-to-mesenchymal transition (EMT), processes that further support CSC survival and metastasis [4,5].

Immune cells: The interaction between CSCs and immune cells within the TME plays a critical role in immune evasion and tumor progression. CSCs can recruit and reprogram immune cells, such as macrophages, neutrophils, and regulatory T cells (Tregs), to create an immunosuppressive environment that protects them from immune attack. Tumor-associated macrophages (TAMs), in particular, secrete pro-inflammatory cytokines and growth factors (e.g., IL-6, TGF-β) that promote CSC stemness and contribute to therapy resistance. Additionally, CSCs can express immune checkpoint molecules, such as PD-L1, that inhibit the activity of cytotoxic T cells, allowing CSCs to evade immune surveillance [6].

Extracellular matrix (ECM): The ECM provides structural support to the tumor and serves as a reservoir for signaling molecules. The biochemical and mechanical properties of the ECM can influence CSC behavior. For example, the stiffness of the ECM has been shown to promote the stem-like properties of CSCs, with mechanotransduction pathways activating YAP/TAZ signaling, which enhances CSC self-renewal. Furthermore, ECM remodeling enzymes, such as matrix metalloproteinases (MMPs), can release growth factors sequestered in the matrix, which subsequently interact with CSCs to promote their proliferation and survival [7,8].

Stromal cells: Cancer-associated fibroblasts (CAFs) are a major component of the TME and play a key role in supporting CSC function. CAFs secrete various factors, such as hepatocyte growth factor (HGF), fibroblast growth factor (FGF), and interleukins, which enhance CSC stemness, EMT, and resistance to apoptosis. CAFs can also remodel the ECM to create a more favorable environment for CSC survival and invasion. Moreover, CAFs have been implicated in the creation of a "niche" that supports the maintenance of CSCs in a quiescent state, which is associated with resistance to chemotherapy [9].

Glycolysis: In hypoxic regions of the tumor, CSCs upregulate glycolysis, which provides rapid energy production and generates metabolic intermediates required for biomass synthesis. Glycolysis also contributes to the acidification of the TME, which can promote the invasive behavior of CSCs and suppress immune cell function.

Oxidative phosphorylation (OXPHOS): In well-oxygenated regions, CSCs can switch to OXPHOS to sustain their energy demands. The dependence on OXPHOS has been observed in certain types of CSCs, such as those in breast cancer, where mitochondrial biogenesis and function are critical for maintaining their stem-like properties. Targeting mitochondrial metabolism in CSCs has emerged as a potential therapeutic strategy to eliminate this resilient cell population [10].

CSC plasticity and the influence of the TME: CSC plasticity refers to the ability of cancer cells to transition between stem-like and non-stem-like states, which is influenced by signals from the TME. For instance, EMT-inducing factors, such as TGF-β and Wnt signaling, can promote the conversion of non-CSCs into CSCs, thereby replenishing the CSC pool. This plasticity enables tumors to maintain a supply of CSCs even after targeted therapies, contributing to tumor relapse and metastasis.

Conclusion

The tumor microenvironment (TME) exerts a profound influence on the behavior, survival, and therapeutic resistance of cancer stem cells (CSCs). Through complex interactions with components such as hypoxia, immune cells, the extracellular matrix, and stromal cells, the TME not only nurtures CSCs but also enhances their stemness, plasticity, and ability to evade treatment. These dynamic interactions create a protective niche for CSCs, facilitating their role in tumor progression, metastasis, and recurrence. Understanding the mechanisms by which the TME sustains CSCs provides valuable insights into potential therapeutic interventions. Targeting the TME, alongside CSCs, holds promise in overcoming therapy resistance and improving long-term cancer outcomes. This approach, focused on disrupting the supportive environment of CSCs, could be pivotal in reducing tumor relapse and providing more effective cancer therapies.

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