IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion.

By V. Gocheva, Hao-wei wang, Bedrick B. Gadea, Tanaya Shree, K. E. Hunter, Alfred L. Garfall, T. Berman, J. Joyce. Genes & Development, 2010

722 citations recorded by the source corpus.

Innate immune cells can constitute a substantial proportion of the cells within the tumor microenvironment and have been associated with tumor malignancy in patients and animal models of cancer; however, the mechanisms by which they modulate cancer progression are incompletely understood. Here, we show that high levels of cathepsin protease activity are induced in the majority of macrophages in the microenvironment of pancreatic islet cancers, mammary tumors, and lung metastases during malignant progression. We further show that tumor-associated macrophage (TAM)-supplied cathepsins B and S are critical for promoting pancreatic tumor growth, angiogenesis, and invasion in vivo, and markedly enhance the invasiveness of cancer cells in culture. Finally, we demonstrate that interleukin-4 (IL-4) is responsible for inducing cathepsin activity in macrophages in vitro and in vivo. Together, these data establish IL-4 as an important regulator, and cathepsin proteases as critical mediators, of the cancer-promoting functions of TAMs.

Subfields: Cancer Research, Immunology and Allergy, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/72c40f4663beee3c18d8f62f63819360e275d6de

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. S. Shalapour
2. A. Mantovani
3. M. Karin
4. D. Hanahan
5. R. Weinberg
6. L. Chávez-Galán
7. I. Garcia
8. Li Yang

In Immunology and Allergy

1. Li Yang
2. R. Weinberg
3. Yi Zhang
4. D. Hanahan

In Molecular Biology

1. M. Karin
2. A. Mantovani
3. S. Shalapour
4. D. Hanahan
5. R. Weinberg
6. L. Chávez-Galán
7. I. Garcia
8. D. Vesin

Citations in the corpus

• Tumor Metastasis: Molecular Insights and Evolving Paradigms (2011, neutral): “Similarly, secretion of IL-4 by breast cancer cells triggers cathepsin protease activity in TAMs, further augmenting carcinoma cell invasiveness (Gocheva et al., 2010).”
• Protective and pathogenic functions of macrophage subsets (2011, result): “These observations are also consistent with the tumour-promoting activities of IL-4 and IL-13, which also promote M2 macrophage differentiatio”
• Tumor associated macrophages and neutrophils in cancer. (2013, background): “For instance, eutrophil-derived MMP-9 has been involved in the angiogenic witch through the release of VEGF from the ECM and neutrophils ere identified as the major source of MMP-9 in human head and eck cancer and hepatocellular carcinoma (Dumitru et al. 2012; uang et al. 2011; Nozawa et al. 2006).”
• Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression and improves chemotherapeutic responses (2012, background): “Previous work by Shree and colleagues (27) and Gocheva and colleagues (47) has illustrated that macrophage-derived cathepsins regulate pancreatic neuroendocrine tumor progression and mammary tumor response to paclitaxel.”
• Immunity, inflammation, and cancer: an eternal fight between good and evil. (2015, positive): “Exposure of macrophages to IL-4 produced by CD4+ T cells and/or cancer cells (59, 63), growth factors such as colony stimulating factor-1 (CSF1) (64), GM-CSF (65), and TGFβ secreted by cancer cells, can also induce the M2 switch.”
• Tumor-associated macrophages: from basic research to clinical application (2017, background): “Consistent with the original description of alternative activation, the type 2 cytokine IL-4 secreted from Th2-polarized CD4 cells [23], IL-10 derived from regulatory T cells (Tregs) [24], and immunoglobulin (Ig) from B cells [25] regulate macrophage polarization to the protumor phenotype.”
• CCL18 from Tumor-Associated Macrophages Promotes Breast Cancer Metastasis via PITPNM3 (2011, positive): “Further mechanistic studies reveal that TAMs promote breast cancer progression and metastasis by releasing a variety of cytokines, including chemokines, inflammatory factors, and growth factors (Condeelis and Pollard, 2006; Gocheva et al., 2010).”
• Macrophage Polarization in Inflammatory Diseases (2014, background): “During the stage of invasion and migration, TAM is converted into M2 phenotype upon the stimulation of IL-4 secreted by CD4+ T cells and tumor cells, and functions as the key to the gate of invasion of tumor cells [74].”