Fig. 3
From: Advances in molecular pathology and therapy of non-small cell lung cancer
Mechanisms involved in cancer cell metastasis in NSCLC. This schematic diagram summarizes the mechanisms involved in cancer cell metastasis in NSCLC. From an evolutionary perspective, metastasis represents a systemic adaptive response to stress within the survival microenvironment. The process begins with several changes in cancer cell characteristics, at least including the activation of oncogenes (e.g., EGFR, ALK, and RAS, etc.), upregulation of cytokines (e.g., IL-6, TGF, IGF, and HIF-1, etc.), chemokines, and their receptors (e.g., CXCL9, CXCL10, CXCL11, CXCR3, CXCR4, and CCR5, etc.), as well as metabolic reprogramming, as detailed in the box. This is followed by phenotypic transformation involving EMT, primarily driven by miRNAs, ZEB1/2, and EZH2. Subsequently, through various soluble molecules and exosomes, the microenvironment of distant organs is altered to support the survival of cancer cells(direct effect). Cancer cells also reeducate bone marrow-derived immune cells, creating an immunosuppressive microenvironment (indirect effect). Additionally, when circulating in the bloodstream, cancer cells co-opt neutrophils and platelets to resist anoikis, and subsequently upregulate adhesion molecules on endothelial cells, facilitating their entry into tissues. In the pre-metastatic niche of distant organs, restoration of MET, ECM remodeling (by MMP2, 9, and 10), induction of angiogenesis (via VEGF, VEGFR, TIE2, and angiopoietin 1/2), and recruitment of CAFs and neuronal cells (via GABA) occur, alongside the engagement of immunosuppressive cells (MDSCs, Tregs, tumor-promoting TANs and TAMs). These cells assist in inducing T cell exhaustion (via PD-(L)1, CTLA-4, LAG3, and TIM3, etc.) and metabolic competition (through upregulation of glutaminases GLS1 and GLS2, and accumulation of toxic cancerous metabolites), enabling the evasion of surveillance by TILs and tissue-resident T cells (αβ or γδ T cells), NK cells, macrophages, and B cells. This complex interplay allows for survival, subclonal evolution, and therapeutic resistance. Without these mechanisms, the tumor may remain dormant for over 10 years before manifesting clinically in distant organs. Note that the pathways and molecules listed do not cover the entire spectrum of the metastatic process, nor do they fully explain the organ-specific nature of metastasis or provide insights into how these contribute to therapeutic resistance
