The lungs are ubiquitous receptacles of metastases originating from various bodily tumors. Although osteopontin (SPP1) has been associated with tumor dissemination, the role of its isoforms in lung-directed metastasis is incompletely understood. We employed syngeneic mouse models of spontaneous and induced lung-targeted metastasis in C57BL/6 mice competent and deficient in both Spp1 alleles. Tumor-derived osteopontin expression was modulated using either stable anti-Spp1 RNA interference, or forced overexpression of intracellular and secreted Spp1 isoforms. Identified osteopontin's downstream partners were validated using lung adenocarcinoma cells conditionally lacking the Trp53 gene and Ccr2-deficient mice. We determined that host-derived osteopontin was dispensable for pulmonary colonization by different tumor types. Oppositely, tumor-originated intracellular osteopontin promoted tumor cell survival by preventing tumor-related protein 53-mediated apoptosis, while the secretory osteopontin functioned in a paracrine mode to accelerate lung metastasis by enhancing tumor-derived C-C-motif chemokine ligand 2 signaling to cognate host receptors. As new ways to target osteopontin signaling are becoming available, the cytokine may constitute an important therapeutic target against pulmonary involvement by cancers of other organs.
Supplementary Table 1 from A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition
Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4+ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1flox/flox × AlbCre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22-IL-22BP axis in HCC.
TH17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of TH17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-β signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in TH17 cells. Our data thus indicate a key function of TH17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of TH17 cells with regard to environmental changes.
Background: The immune cells that facilitate malignant pleural effusion (MPE), an immune-mediated end-stage cancer manifestation (Stathopoulos, G.T. et al. Am J Respir Crit Care Med 2012;186:487-92), have not been identified. Aims: We found mast cells (MC) in MPE and investigated their functions. Methods: Human and experimental MPE were assessed for MC content.MPE was induced by intrapleurally injected Lewis lung (LLC) and MC38 colon adenocarcinoma cells in Wt and two separate strains of MC-deficient (cKitWsh, Cpa3.Cre) mice. Bone marrow-derived MC were used for MC cell fate and restoration studies. Tumor cells and tumor-exposed MC were subjected to transcriptional profiling. Results: We discovered and characterized MC in human and murine MPE. Cell fate models conveyed that MC were attracted to MPE by tumor-derived CCL2 to be locally degranulated by osteopontin. Both cKitWsh and Cpa3. Cre mice were protected from MPE induced by both LLC and MC38 cells (mean±SD MPE volume of C57BL/6, cKitWsh and Cpa3. Cre mice induced by LLC cells: 573±242, 108±130, and 277±284µL; and by MC38 cells: 864±310, 278±323, and 464±203 µL; n = 7-23/group; P<0.001 for both comparisons by one-way ANOVA). MPE MC secreted tryptase AB1 to promote vascular leakiness and interleukin-1β to augment tumor growth. The latter functioned to fuel nuclear factor-κβ in tumor cells, since IKKβ-overexpressing tumor cells were autonomous from MC for nuclear factor-κβ activation and MPE. Conclusions: Adenocarcinomas instate circuitry with MC to induce MPE once metastatic in the pleural space. Acknowledgements: Supported by ERC-2010-StG-#260524 anda Hellenic Thoracic Society 2012 Research Award.
Supplementary Figure Legends 1-2 from A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition
