Extracellular vesicles in non-small cell lung cancer stemness and clinical applications

Abstract

Non-small cell lung carcinoma (NSCLC) accounts for 85% of lung cancers, the leading cause of cancer associated deaths in the US and worldwide. Within NSCLC tumors, there is a subpopulation of cancer cells termed cancer stem cells (CSCs) which exhibit stem-like properties that drive NSCLC progression, metastasis, relapse, and therapeutic resistance. Extracellular vesicles (EVs) are membrane-bound nanoparticles secreted by cells that carry vital messages for short- and long-range intercellular communication. Numerous studies have implicated NSCLC CSC-derived EVs in the factors associated with NSCLC lethality. In this review, we have discussed mechanisms of EV-directed cross-talk between CSCs and cells of the tumor microenvironment that promote stemness, tumor progression and metastasis in NSCLC. The mechanistic studies discussed herein have provided insights for developing novel NSCLC diagnostic and prognostic biomarkers and strategies to therapeutically target the NSCLC CSC niche.

Keywords: biomarkers; cancer stem cells; extracellular vesicles; metastasis; non-small cell lung cancer; oncogenic signaling; therapeutic targeting; tumor microenvironment.

Figure 1

Hallmark characteristics of NSCLC CSCs that drive tumor biological processes. 1) CSCs can propagate tumors due to their self-renewal and proliferation ability. 2) The self-renewal and high plasticity of CSCs are thought to be associated with epithelial-to-mesenchymal transition. 3) CSCs have a higher propensity to invade, which is important to drive tumor progression beyond the primary site. 4) Stem-cell-associated signaling pathways allow a single CSC to proliferate and form tumor spheres in vitro. 5) CSCs can initiate and propagate tumors with characteristics of the original tumor. 6) Due to intrinsic ability to stay in a quiescent state, efficiently repair DNA damage, manage redox stress, and express multi-drug transporters, CSCs contribute to resistance to chemotherapy and radiation therapy, which often results in NSCLC tumor relapse. 7) CSCs inhibit immune cell activation to generate an immunosuppressive environment and contribute to immune checkpoint therapy failure. Created with BioRender.com.

Figure 2

Bidirectional EV-mediated communication in NSCLC progression: NSCLC TME consists of different cell types such as differentiated cancer cells or bulk cancer cells (BCC), cancer stem cells (CSC), cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), mesenchymal stem cells (MSCs). All of these cells can release EVs with unique cargo that is internalized by other cells of the tumor to regulate its behavior. For example, (clockwise right to left) Red EVs: Tumor-derived EVs or BCC-derived EV cargo, including miRNA, lncRNA, and circRNA can promote drug resistance and stemness. BCCs also secrete PD-L1-containing EVs that inactivate CD8+ T cells and promote drug resistance. Green EVs: TAMs, when polarized to M2, secrete EVs to promote proliferation and metastasis by transferring LINC000273 and reciprocally, BCC-derived EV cargo miR-19b-3p can induce M2 polarization. Purple EVs: MSCs-derived EV mediated transfer of miR-210-3p, miR-191-a and miR-5100 to BCC promote their invasion and metastasis. Orange EVs: CAFs can induce de-differentation and stemness by transferring IL-6 and Activin-A to BCCs. CAFs can also support CSC growth by secreting IGF11. Blue EVs: CSC-derived EVs carry ncRNA such as lnc-ROLLCSC, lnc-Mir100hg, miR-210-3p, and miR-21-5p which promote invasion, metastasis, and miR-1246 which promote stemness and drug resistance in BCCs.