EV-Mediated Chemoresistance in the Tumor Microenvironment: Is NF-κB a Player?

Abstract

Drug resistance is a major impediment to patient survival and remains the primary cause of unsuccessful cancer therapy. Drug resistance occurs in many tumors and is frequently induced by chemotherapy which triggers a defensive response both in cancerous and cancer-associated cells that constitute the tumor microenvironment (TME). Cell to cell communication within the TME is often mediated by extracellular vesicles (EVs) which carry specific tumor-promoting factors able to activate survival pathways and immune escape mechanisms, thus sustaining tumor progression and therapy resistance. NF-κB has been recognized as a crucial player in this context. NF-κB activation is involved in EVs release and EVs, in turn, can trigger NF-κB pathway activation in specific contexts, based on secreting cytotype and their specific delivered cargo. In this review, we discuss the role of NF-κB/EVs interplay that sustain chemoresistance in the TME by focusing on the molecular mechanisms that underlie inflammation, EVs release, and acquired drug resistance.

NF-κB: Governing Macrophages in Cancer

“…It is known that the intercellular communication between TAMs, TME and several cancer cells, including breast cancer cells, is also mediated by EVs [122]. A recent study uncovered that TAM-derived EVs enriched with miR-660 inhibit Kelch-like protein 21 (KLHL21) in breast cancer cells leading to the activation of NF-κB p65 signaling pathway.…”

“…Several pieces of evidence showed that TAMs sustain the initiation and progression of CRC by regulating several processes including tumor proliferation, metabolism, immunosuppression, angiogenesis and metastasis [124]. In CRC, intratumoral macrophages exert tumor-promoting functions, while TAMs found in the tumor invasive front correlate with better prognosis [122,123]. However, mixed macrophage populations are observed in human colorectal cancer tumors [125].…”

NF-κB: Governing Innate Immunity in Cancer

“…It is known that the intercellular communication between TAMs, TME and several cancer cells, including breast cancer cells, is also mediated by EVs [115]. A recent study uncovered that TAMderived EVs enriched with miR-660 inhibit Kelch-like Protein 21 (KLHL21) in breast cancer cells leading to the activation of NF-κB p65 signaling pathway.…”

“…Several evidence showed that TAMs sustain the initiation and progression of CRC by regulating several processes including tumour proliferation, metabolism, immunosuppression, angiogenesis and metastasis [117]. In CRC intratumoral macrophages exert tumor-promoting functions while TAMs found in the tumour invasive front correlate with better prognosis [115,116]. However, mixed macrophage populations are observed in human colorectal cancer tumours [118].…”