Tunneling nanotubes, a novel mode of tumor cell–macrophage communication in tumor cell invasion

Abstract

The interaction between tumor cells and macrophages is crucial in promoting tumor invasion and metastasis. In this study, we examined a novel mechanism of intercellular communication, namely membranous actin-based tunneling nanotubes (TNTs), that occurs between macrophages and tumor cells in the promotion of macrophage-dependent tumor cell invasion. The presence of heterotypic TNTs between macrophages and tumor cells induced invasive tumor cell morphology, which was dependent on EGF-EGFR signaling. Furthermore, reduction of a protein involved in TNT formation, M-Sec (TNFAIP2), in macrophages inhibited tumor cell elongation, blocked the ability of tumor cells to invade in 3D and reduced macrophage-dependent long-distance tumor cell streaming in vitro. Using an in vivo zebrafish model that recreates macrophagemediated tumor cell invasion, we observed TNT-mediated macrophage-dependent tumor cell invasion, distant metastatic foci and areas of metastatic spread. Overall, our studies support a role for TNTs as a novel means of interaction between tumor cells and macrophages that leads to tumor progression and metastasis.

Potential hydrodynamic cytoplasmic transfer between mammalian cells: Cell-projection pumping

“…Cancer rarely generates new biology, but instead usually perverts established mechanisms. From this, and given altered phenotype following cytoplasmic transfer (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)19), we suggest CPP may contribute to cell differentiation and phenotypic control in other biological settings including: embryogenesis, development, inflammation and wound healing.…”

“…For example, exosome uptake alters cell morphology (14,15,42), but we find no literature of TNT mediating this effect. Similarly, while exosomes from a variety of sources can increase migration of several cell types (16,(43)(44)(45)(46), there is less evidence for a similar effect for cellular contents transferred via TNT (17). Seemingly different effects of cytoplasmic transfer by CPP and TNT, underscore the distinction between the two processes.…”

“…We earlier described the exchange of membrane and cytoplasmic protein between cultured human fibroblasts (Fib) and malignant cells (MC) (1). Others have made similar observations, and describe this as via either tunneling nanotubes (TNT) or exosomes and other shed membrane vesicles, and this is often associated with changes in cell phenotype (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), while we have also seen phenotypic change (1,18). Mitochondrial exchange has been considered particularly interesting (2,4,5,19).…”

Tyrosine kinase inhibitors and interferon‐α increase tunneling nanotube (TNT) formation and cell adhesion in chronic myeloid leukemia (CML) cell lines

“…They are involved in cell‐to‐cell interaction and intercellular transport of organelles and pathogens such as virus and bacteria . Leukocytes, their leukemic counterparts and bone marrow stromal cells have all been reported to form TNTs in vitro . TNT is proposed to be a mechanism for chemo resistance by transport of oncoproteins between T and B cells as well as in colon cancer cells, by transfer of mitochondria from endothelial cells to chemotherapy exposed cancer cells, or by induced drug‐efflux in aggressive forms of pancreatic carcinoma .…”

“…16,[18][19][20][21][22][23][24] Leukocytes, their leukemic counterparts and bone marrow stromal cells have all been reported to form TNTs in vitro. [25][26][27][28][29][30][31][32] TNT is proposed to be a mechanism for chemo resistance by transport of oncoproteins between T and B cells as well as in colon cancer cells, by transfer of mitochondria from endothelial cells to chemotherapy exposed cancer cells, or by induced drug-efflux in aggressive forms of pancreatic carcinoma. [33][34][35][36][37][38] The impact of TNTs in vivo is so far not well characterized, but they have been described to connect myeloid cells in the cornea of mouse 39,40 and in fresh resected tumor samples from patients with malignant pleural mesothelioma and lung adenocarcinoma.…”