Table of Contents
Introduction:
The overall complexity of tumors complicates the development of effective cancer therapies. Tumor heterogeneity is aggravated during cancer progression with the maturation of the cellular and non-cellular components of the tumor niche, namely the Tumor microenvironment (TME). The TME is composed of extracellular matrix (ECM), stromal cells (fibroblasts, mesenchymal stromal cells, pericytes, possibly adipocytes, blood, and lymphatic networks, etc.), and immune cells (T and B lymphocytes, natural killer cells, tumor cells, and others). It is becoming increasingly clear that TME determines abnormal tissue function and plays an important role in subsequent malignant development.
What Does Targeting the Tumor Microenvironment Mean?
Chemotherapy is a cancer treatment used worldwide and is often combined with surgery or surgery and radiation therapy, depending on the stage of the tumor. Since the discovery of several key mutations that contribute to cancer development (e.g., Epidermal growth factor receptor (EGFR), p53, c-Myc), these have become targets for more selective anticancer drug development widely used. Despite the effectiveness of these agents, Multidrug resistance (MDR) is on the rise, often leading to tumor recurrence and poor patient quality of life. Cancer research has now focused on tumor cells, but there is growing evidence that the action of TMEs plays a crucial role in tumor progression and MDR. In late-stage solid tumors, the tumor microenvironment is highly complex and heterogeneous. First, the genomic profile of tumor cells is crucial for the regulation of the tumor environment. The rapid proliferation of tumor cells triggers multiple phenomena like hypoxia, leading to metabolic reprogramming of tumor cells and adaptation of her TME to new situations. Interactions between cancer cells and neighboring cells, including stromal cells and cells of the immune system (often caused by inflammation at the tumor site), lead to further changes in TME cellular components, remodeling of the extracellular matrix, and It leads to the formation of a chaotic angiogenic system. May cause metastasis. During tumor growth, cancer cells and TME components continually adapt to environmental conditions, influencing overall tumor growth.
What Are the Current Strategies Used to Target TME Components?
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Targeting Extracellular Matrix: The composition of the Extracellular matrix (ECM) is of great importance for the prognosis of certain tumors. The ECM is a three-dimensional structure composed of collagen, elastin, fibronectin, hyaluronic acid, proteoglycans, and glycoproteins that encapsulate cells and support tissues by providing hydration and pH homeostasis. In addition, the ECM also acts as a reservoir for growth factors. Under normal conditions, the ECM divides into a stromal matrix, which contains stromal cells that form connective tissue, and a basement membrane, a specialized layer that separates epithelial and endothelial cells from the underlying stroma of epithelial tissue.
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Targeting Hypoxia and Acidosis: The rapid proliferation of tumor cells is associated with high oxygen demands that cannot be met by the surrounding blood supply, resulting in limited cellular oxygen availability and hypoxia. The partial pressure of oxygen within the TME is typically lower than in normal tissue. In addition, two types of hypoxia can occur in TME, chronic and acute/cyclic hypoxia. Chronic hypoxia occurs when oxygen diffusion is limited by a large diffusion distance or the geometry of veins that makes diffusion difficult. Acute hypoxia, on the other hand, occurs when transient perfusion occurs, such as vascular occlusion caused by cell aggregation.
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Avoiding Neovascularization-Targeting the Endothelial Cells and Pericytes: In the early stages of epithelial tumors, disorganized aggregates of proliferating tumor cells are separated from connective tissue by a basal layer, which limits oxygen and nutrient supply to highly proliferating cells. Hypoxia in growing tumor cells induces the release of angiogenic signals such as Vascular endothelial growth factor A (VEGFA). Upon binding to VEGF receptor 2 (VEGFR-2) on the surface of the endothelial cells of adjacent cells, it induces endothelial cell angiogenic responses.
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Targeting Immune System: The tumor cell environment is characterized by chronic overexpression of inflammatory mediators, making it difficult for the immune system to recognize and eliminate aberrant cells. Immune cells become unresponsive to tumor cells. In cancer’s immune system, several measures are used to combat tumor progression:
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It inhibits the recruitment of macrophages to tumor tissue.
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Inhibition of macrophage differentiation towards the pro-neoplastic phenotype.
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Targets chronic inflammatory or tumorigenic factors provided by adaptive immune cells.
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Activates anti-tumor activity to avoid carcinogenic risks and poor patient prognosis when tumors are already established.
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Targeting Cancer-Associated Fibroblasts: The migration, proliferation, and secretory activity of stromal cells within the ECM are required for proper tissue function within the organ. Mesenchymal stromal cells are a highly heterogeneous population of progenitor cells of diverse origins that are found in most adult tissues and play a ubiquitous role in tumor progression. Mesenchymal stromal cells are involved in collagen turnover and possess ECM remodeling properties, including the ability to differentiate into non-hematopoietic cells.
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Targeting Exosomes: Communication between cells within the TME can be paracrine (between cells of different types located in the same anatomical region), autocrine (between cells of the same kind), and even endocrine (between different types of cells located in different anatomical regions) are important for the regulation of cellular/molecular events involved in TME maturation. Resident cells within the TME communicate with each other primarily through cytokines, chemokines, and growth factors. Expression of cytokines by tumor cells is often accompanied by expression of the corresponding receptors.
What Is the Case of Combined Therapies?
Monotherapy approaches are widely used, while combination approaches have been extensively studied in clinical trials and are considered key to cancer treatment. Previously, these combinations were based on cytotoxic agents, but now this has also been applied to targeted therapeutic agents such as monoclonal antibodies and small molecule kinase inhibitors, which are also more effective in combination. Multiple pathways can be addressed through this type of approach, thus avoiding MDR and the associated low toxicity.
What Are Nanomedicines?
Nanotechnology revolutionized many areas of science, and medicine was undoubtedly one of them, later known as nanomedicine. Nanomedicine, which consists of particles of various sizes and shapes, consists of a variety of materials with amazing physicochemical properties at the nanoscale and is of great interest for applications in the field of diagnostics and therapeutics. Materials range from inorganic materials such as gold, iron oxide, silver, and silicon dioxide to organic materials such as lipid-based, cell membrane-derived, and layered composites.
What Are the Models for the Study of TME?
FDA-approved anticancer agents are typically optimized to be highly effective in vitro using cancer cell monolayers and in vivo using mouse xenograft cancer models. However, given the complexity of the tumor, there is a gap between these two models. Indeed, the development of innovative therapeutics for effective cancer treatment requires suitable preclinical models mimicking TME.
Conclusion:
Fundamental research to understand TME is essential for the development of new models that enable the validation of novel therapeutic approaches. Tumor cells are now known to behave very differently when surrounded by a malignant microenvironment than when they are themselves. This TME influences surface receptors expressed, signaling pathways activated or repressed, and influences therapeutic efficacy/response.
