The tumor microenvironment (TME) is a complex and dynamic network consisting of tumor cells, immune cells, stromal cells, extracellular matrix (ECM), cytokines, and growth factors, all interacting to influence tumorigenesis, progression, and metastasis. Long non-coding RNAs (lncRNAs), a class of non-coding RNAs longer than 200 nucleotides, have recently garnered significant attention for their role in regulating gene expression within the TME. They contribute to crucial processes such as immune evasion, angiogenesis, metabolic reprogramming, and the maintenance of cancer stem cells, and their influence extends across transcriptional, post-transcriptional, and epigenetic levels.
This review aims to provide an in-depth understanding of the roles of lncRNAs in shaping the TME and their potential as therapeutic targets. By modulating key signaling pathways and cellular interactions within the TME, lncRNAs are involved in processes critical to tumor progression, such as remodeling of the ECM, immune cell infiltration, angiogenesis, and stromal-tumor communication. Furthermore, the review explores the potential of lncRNAs as biomarkers for early cancer detection and prognosis, as well as challenges in targeting them for therapeutic interventions.
lncRNAs and Tumor Microenvironment Dynamics
lncRNAs mediate the interactions between tumor cells and their surrounding microenvironment, influencing several aspects of tumor behavior. These interactions include the promotion of tumor cell proliferation, migration, angiogenesis, and immune evasion, as well as the modulation of stromal cell activities. Tumor cells often secrete lncRNAs into the surrounding stroma, where they can bind to receptors on stromal cells and alter their behavior, thus reinforcing tumor cell growth and survival. For example, lncRNAs secreted by tumor cells can stimulate the transformation of fibroblasts into tumor-associated fibroblasts (TAFs), enhancing the pro-tumorigenic potential of the TME.
Moreover, lncRNAs can affect immune cell function within the TME by promoting immunosuppressive conditions, thereby facilitating tumor immune evasion. They can also influence angiogenesis by modulating the expression of angiogenic factors in both tumor cells and endothelial cells. Through these mechanisms, lncRNAs regulate key processes like tumor growth, metastasis, and resistance to therapies, positioning them as critical modulators of tumor biology.
lncRNAs in Tumor-Associated Fibroblasts (TAFs)
Tumor-associated fibroblasts (TAFs) are key stromal components of the TME, influencing tumor progression and therapy resistance. lncRNAs play a significant role in mediating the crosstalk between TAFs and tumor cells. For instance, the lncRNA LOC100506114 is upregulated in TAFs from oral squamous cell carcinoma, promoting fibroblast transformation and enhancing tumor cell proliferation and migration. Similarly, the overexpression of lncRNAs like MALAT1 in TAFs has been linked to enhanced migration and invasiveness of ovarian epithelial carcinoma cells.
TAFs are also involved in the development of therapy resistance. For example, the lncRNA DNM3OS is upregulated in esophageal cancer by TAFs and enhances DNA damage response pathways, contributing to resistance against radiotherapy. These findings highlight the critical role of lncRNAs in facilitating TAF-mediated tumor progression and resistance to cancer treatments.
lncRNAs and Angiogenesis
Angiogenesis is a crucial process in tumor growth and metastasis, as it provides tumors with the nutrients and oxygen necessary for expansion. lncRNAs have been identified as key regulators of angiogenesis within the TME. For example, in breast cancer, the lncRNA NR2F1-AS1 is correlated with the expression of endothelial cell markers CD31 and CD34, promoting angiogenesis. In gastric cancer, the upregulation of the lncRNA PVT1 enhances VEGFA expression, which in turn stimulates angiogenesis, further supporting tumor growth and metastasis.
Targeting lncRNAs that regulate angiogenesis offers a promising therapeutic approach. For instance, the inhibition of lncRNAs like LINC00173.v1 has been shown to reduce angiogenesis and increase the sensitivity of lung cancer cells to chemotherapy, suggesting that lncRNAs could be targeted to disrupt the blood supply to tumors.
lncRNAs and Tumor-Associated Immune Cells
The interaction between tumor cells and tumor-associated immune cells, such as macrophages, T cells, and natural killer (NK) cells, is vital for determining the tumor’s response to treatment. lncRNAs play a central role in modulating these immune cells within the TME, often facilitating immune evasion. For example, in breast cancer, the lncRNA HISLA is transferred from tumor-associated macrophages (TAMs) to tumor cells via exosomes, promoting glycolysis and anti-apoptotic pathways, which enhances tumor survival and chemoresistance.
Similarly, lncRNAs like NEAT1 and MALAT1 can modulate immune checkpoints on T cells, impairing their function and enabling tumors to escape immune surveillance. By regulating immune cell behavior, lncRNAs not only contribute to tumor progression but also present new targets for therapeutic intervention aimed at reversing immune suppression within the TME.
Exosomal lncRNAs and Tumor Progression
Exosomes, small vesicles released by cells, play a key role in intercellular communication within the TME. lncRNAs encapsulated in exosomes can be transferred between tumor and stromal cells, modulating processes such as angiogenesis, metastasis, and chemotherapy resistance. For instance, the lncRNA CRNDE is transferred from TAMs to gastric cancer cells via exosomes, where it promotes the degradation of PTEN, a tumor suppressor gene, thereby enhancing tumor cell survival and resistance to chemotherapy.
The transfer of lncRNAs via exosomes not only facilitates tumor progression but also provides a potential avenue for therapeutic intervention. Targeting exosomal lncRNAs could disrupt the pro-tumorigenic interactions within the TME, thereby inhibiting tumor growth and improving treatment outcomes.
Clinical Implications and Therapeutic Potential
lncRNAs are emerging as promising biomarkers for cancer diagnosis and prognosis due to their tissue-specific expression patterns and stability in body fluids. They offer significant potential for non-invasive early cancer detection. Furthermore, lncRNAs are being explored as therapeutic targets to disrupt tumor-stroma interactions, reverse drug resistance, and enhance the efficacy of existing treatments such as chemotherapy and immunotherapy. Strategies such as antisense oligonucleotides, RNA interference, and CRISPR-based techniques are being developed to specifically target lncRNAs in the TME.
However, challenges remain in targeting lncRNAs therapeutically, including ensuring specificity, minimizing off-target effects, and optimizing delivery systems. Advances in nanotechnology and CRISPR-based platforms offer promising solutions to these challenges, enabling the precise delivery of lncRNA-targeted therapies.
Conclusion
Long non-coding RNAs play a crucial role in regulating tumor progression within the tumor microenvironment. They influence key processes such as angiogenesis, immune evasion, metastasis, and drug resistance. Targeting lncRNAs represents a promising therapeutic strategy to disrupt tumor-stroma interactions and enhance the effectiveness of current treatments. As research continues to uncover the complex roles of lncRNAs in cancer biology, these molecules hold the potential to revolutionize cancer diagnosis and treatment, offering new hope for patients with advanced and treatment-resistant cancers.
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The study was recently published in the Gene Expression.
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