In recent years, long non-coding RNAs (lncRNAs) have emerged as pivotal players in tumor biology, with their influence extending across various processes within the tumor microenvironment (TME). These molecules, which surpass 200 nucleotides in length, are instrumental in modulating gene expression and contributing to crucial mechanisms such as immune evasion, angiogenesis, metabolic reprogramming, and cancer stem cell maintenance. This article delves into the multifaceted roles of lncRNAs in shaping the TME and their potential as therapeutic targets, exploring their impact on signaling pathways, cellular interactions, and clinical applications.
Within the complex network of the TME, lncRNAs mediate interactions between tumor cells and their surrounding environment, influencing tumor behavior at multiple levels. For instance, they promote tumor cell proliferation, migration, and angiogenesis while also altering the activities of stromal cells. One significant mechanism involves the secretion of lncRNAs by tumor cells into the surrounding stroma, where they bind to receptors on stromal cells, reinforcing tumor growth and survival. Additionally, lncRNAs contribute to the transformation of fibroblasts into tumor-associated fibroblasts (TAFs), enhancing the pro-tumorigenic potential of the TME.
Moreover, lncRNAs play a critical role in immune cell function within the TME, often fostering immunosuppressive conditions that facilitate tumor immune evasion. They also influence angiogenesis by modulating the expression of angiogenic factors in both tumor and endothelial cells. Studies have shown that certain lncRNAs, such as NR2F1-AS1 in breast cancer and PVT1 in gastric cancer, correlate with enhanced angiogenesis, further supporting tumor growth and metastasis.
Exosomal lncRNAs further complicate the landscape of intercellular communication within the TME. Encapsulated in exosomes, these molecules can be transferred between tumor and stromal cells, modulating processes like angiogenesis, metastasis, and chemotherapy resistance. For example, the transfer of CRNDE from tumor-associated macrophages to gastric cancer cells promotes the degradation of PTEN, a tumor suppressor gene, thereby enhancing tumor survival and resistance to treatment.
From a clinical perspective, lncRNAs hold immense promise as biomarkers for cancer diagnosis and prognosis due to their tissue-specific expression patterns and stability in body fluids. Researchers are actively exploring strategies to target lncRNAs using antisense oligonucleotides, RNA interference, and CRISPR-based techniques, aiming to disrupt tumor-stroma interactions, reverse drug resistance, and enhance treatment efficacy.
As research continues to illuminate the intricate roles of lncRNAs in cancer biology, these molecules could revolutionize diagnostic and therapeutic approaches for advanced and treatment-resistant cancers. By targeting lncRNAs, scientists hope to dismantle the complex network of interactions within the TME, paving the way for more effective treatments and improved patient outcomes.