Introduction:
The tumor microenvironment (TME) has emerged as a major player in the landscape of cancer research, particularly in the context of oral cancer. Beyond the tumor cells themselves, the TME encompasses a dynamic milieu of surrounding cellular and non-cellular components that interact intricately to influence tumor behavior. In oral cancer, this microenvironment exerts profound effects on various aspects of disease progression, including tumor initiation, growth, invasion, and metastasis. Understanding the complex interplay within the TME is crucial for unraveling the underlying mechanisms driving oral cancer pathogenesis and for devising targeted therapeutic strategies to combat this formidable disease.
What Is the Tumor Microenvironment?
Virchow et al. proposed a significant link between inflammation and cancer, emphasizing the concept of the tumor microenvironment, which highlights the direct association between the development of tumor cells and bodily or organ inflammation. In oral pathology research, there has been a substantial focus on exploring how inflammation contributes to the initiation and progression of oral cancer cells. This research delves into various aspects, including:
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Investigating the precise mechanisms underlying tumor genesis.
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Understanding the processes through which tumor cells may eventually develop.
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Assessing the ability of tumor cells to proliferate continuously or metastasize to other parts of the body. For instance, highly aggressive oral cancers have the potential to metastasize to areas such as the facial sinuses, brain cavity, neck, or other organs like the colon and kidneys, among others, through metastatic spread.
How Does Tumor Microenvironment Research Help in Managing Oral Cancers?
The tumor microenvironment plays a crucial role in determining the prognosis of individuals with cancer. Eliminating the tumor microenvironment would halt not only the proliferation and spread of cancer cells but also their metastatic potential. Aggressive oral cancers are particularly concerning due to their ability to metastasize to other organs and evade both drug treatments and the body's natural immune responses. In 1863, Virchow et al. first proposed the concept of the tumor microenvironment, which has since been supported by extensive research demonstrating that the environment in which cancer cells grow can significantly influence their behavior and growth rates.
Early-stage oral cancer offers an opportunity to intervene and suppress tumor growth by targeting the tumor microenvironment. Immediate treatment strategies may include a combination of drugs, surgery, and immunotherapy, with chemotherapy and radiotherapy serving as supplementary options. This comprehensive approach aims to effectively restrain the tumor microenvironment and improve patient outcomes.
Researchers have observed that during drug treatment or cancer elimination in the initial stages, the tumor microenvironment (TME) gradually diminishes significantly, leading to a halt in cancer cell growth. Medical research highlights the interdependence between oral tumors and their microenvironment, with the microenvironment serving as a crucial factor that can influence patient survival rates. Maxillofacial surgeons can strategically aim to reduce or eliminate the cancer environment during treatment planning, as doing so not only targets the cancer cells directly but also disrupts their supportive surroundings. This approach, whether through surgical intervention, chemotherapy, radiotherapy, or immunotherapy, holds promise for improving patient outcomes by effectively neutralizing the antagonistic factors within the TME.
What Are the Components Altered in the Tumor Microenvironment?
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All tissues, whether oral soft tissue or hard tissue, consist of the extracellular matrix (ECM). The interaction between tumor or cancer cells and the ECM of tissues can activate specific signaling pathways in the body. In the context of moderate to aggressive oral cancers, oral surgeons and oncologists must have a thorough understanding of ECM dysregulation. This knowledge not only helps in identifying potential cancer cells but also guides the selection of surgical or non-surgical therapeutic targets for tumor elimination.
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Collagen makes up nearly 90 percent of the human extracellular matrix, forming macromolecules through cross-linking between molecules.
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Matrix metalloproteinases (MMPs) are enzymes directly involved in the physiological and pathological degradation of collagen. During collagen degradation by MMPs, various signaling molecules are released, altering the tumor microenvironment (TME). Collagen is a major component of the tumor ECM in oral tissues, capable of directly impacting tumor cell proliferation and intercellular signaling pathways. This highlights the significant role of ECM components, particularly collagen, in shaping the TME and influencing cancer progression.
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Fibronectin, although expressed at lower levels in most oral cancers, plays a significant role in the tumor microenvironment (TME) based on oral pathologic research. Despite its minor presence, fibronectin contributes to various functions within the extracellular matrix (ECM) of tissues. These functions include cell adhesion, migration, proliferation, vascularization, and even the formation of structural proteins within the ECM. Despite its lower expression, fibronectin is implicated in the malignant transformation of oral tissues, highlighting its importance in the TME.
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Elastin is another crucial component found in elastic fibers, prevalent in ligaments and vascular walls throughout the body. Working in conjunction with collagen, elastin maintains the strength of bodily tissues by enhancing resistance to deformation and breaking forces. When cancer cells proliferate or metastasize, alterations in elastin are likely, potentially impacting tissue integrity and elasticity. This underscores the significance of elastin in the context of cancer progression and its influence on tissue mechanics within the TME.
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Laminin proteins, in conjunction with collagen, comprise the basement membrane of cells and play a role in the vascularization process. Laminin is considered another crucial element affected within the tumor microenvironment (TME).
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Hyaluronic acid (HA), a major component of the ECM in oral tissues, serves several important functions for healthy cells. These include regulating vascular wall permeability, aiding in oral wound healing, facilitating material diffusion, and transporting substances across cell membranes. HA contributes to the elastic viscosity of the ECM and acts as a vital reservoir for water retention. When these normal cellular functions are disrupted by malignant tumors or cancer cell transformation, the tumor microenvironment may promote cell proliferation or metastatic potential.
Conclusion:
It is crucial for oral and maxillofacial surgeons, as well as oncologists, to recognize that the occurrence, development, and metastasis of oral tumors are intricately linked to the tumor microenvironment (TME) of oral cancer cells. Various factors within the TME influence the growth and replication of cancer cells, including the structure, function, and metabolism of the tumor tissue within the oral environment. As we have discussed earlier, components of the extracellular matrix (ECM) such as collagen, fibronectin, laminin, and hyaluronic acid, play critical roles in shaping the TME and affecting tumor behavior. Additionally, factors such as inflammation, immune cell activity, and signaling pathways contribute to the dynamic nature of the TME and impact cancer progression. Understanding these complex interactions is essential for devising effective treatment strategies tailored to target the specific vulnerabilities within the TME of oral cancers.
