Macrophage-Secreted TNFα and TGFβ1 Influence Migration Speed and Persistence of Cancer Cells in 3D Tissue Culture via Independent Pathways
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Abstract
The ability of a cancer cell to migrate through the dense extracellular matrix within and surrounding the solid tumor is a critical determinant of metastasis. Macrophages enhance invasion and metastasis in the tumor microenvironment, but the basis for their effects is not fully understood. Using a microfluidic 3D cell migration assay, we found that the presence of macrophages enhanced the speed and persistence of cancer cell migration through a 3D extracellular matrix in a matrix metalloproteinases (MMP)-dependent fashion. Mechanistic investigations revealed that macrophage-released TNFα and TGFβ1 mediated the observed behaviors by two distinct pathways. These factors synergistically enhanced migration persistence through a synergistic induction of NF-κB–dependent MMP1 expression in cancer cells. In contrast, macrophage-released TGFβ1 enhanced migration speed primarily by inducing MT1-MMP expression. Taken together, our results reveal new insights into how macrophages enhance cancer cell metastasis, and they identify TNFα and TGFβ1 dual blockade as an antimetastatic strategy in solid tumors. Cancer Res; 77(2); 279–90. ©2016 AACR.
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TAMs influence the migration rate of cancer cells by TGFβ1-induced MT1-MMP and cancer cell migration persistence by NF-κB-dependent MMP1 expression.
“It could be shown that TAM influences the migration rate of cancer cells by TGFβ1-induced MT1-MMP and the cancer cell migration persistence by the nuclear factor Kappa - light chain enhancer of activated B cells (NF-κB)-dependent MMP1 expression.”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [110]
Tri-culture of brain ECs with pericytes and astrocytes was essential for maintaining BBB phenotypes such as narrow vascular morphology, low vascular permeability, and functional efflux transporter.
“It was confirmed that tri‐culture of brain ECs with pericytes and astrocytes was essential for maintaining BBB phenotypes such as narrow vascular morphology, low vascular permeability, and functional efflux transporter.”
From 3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip (2023) · cites this paper as [151]
The Introduction and Discussion passages describe macrophages and cancer-cell migration in 3D collagen, not a blood–brain barrier model. Searches for brain endothelial-cell tri-culture and for BBB permeability and efflux transporters found no passage addressing the claim; page numbers were not provided. (LLM, conf=0.78)
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References 52 · Cited by 100
Research works printed but not linked: 3
- Maheshwari G, Lauffenburger Da. Deconstructing (and reconstructing) cell migration. Microsc Res Tech. 1998; 43:358-368. [PubMed: 9858333]
- Chong H, Vodovotz Y, Cox GW, Barcellos-Hoff MH. Immunocytochemical localization of latent transforming growth factor-beta1 activation by stimulated macrophages. J Cell Physiol. 1999; 178:275-283. [PubMed: 9989773]
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- Authors
- Li, R., Hebert, J. D., Lee, T. A., Xing, H., Boussommier-Calleja, A., Hynes, R. O., Lauffenburger, D. A., & Kamm, R. D.
- Affiliations
- Massachusetts Institute of Technology (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Corresponding author
- Kamm, Roger D.
- ORCID
- Venue
- Cancer Research
- Published
- 2017-01-15
- Volume
- 77
- Issue
- 2
- Pages
- 279-290
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5243269
- OpenAlex
- W2554275541
- Cited by
- 100
- References
- 52
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 10 · 2023: 11 · 2022: 13 · 2021: 7 · 2020: 21 · 2019: 15 · 2018: 11 · 2017: 4
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (U01 CA202177-01, T32GM007287)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- macrophages, TNF-α, TGF-β1, tumor cell migration, metastasis, tumor microenvironment, 3D extracellular matrix, matrix metalloproteinases, MMP-1, MT1-MMP, NF-κB, migration speed, migration persistence, anti-metastatic therapy
- MeSH terms
- Cell Movement, Humans, Macrophages, Neoplasm Invasiveness, Tumor Necrosis Factor-alpha, Blotting, Western, Matrix Metalloproteinases, Cell Line, Tumor, Microfluidic Analytical Techniques, Tissue Culture Techniques, Transforming Growth Factor beta1, Real-Time Polymerase Chain Reaction
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