Previous studies have linked cancer cell-associated ADAM28 expression with tumor progression and metastatic dissemination. However, the role of host-derived ADAM28 in cancer dissemination processes ...remains unclear. Genetically engineered-mice fully deficient for ADAM28 unexpectedly display increased lung colonization by pulmonary, melanoma or breast tumor cells. In experimental tumor cell dissemination models, host ADAM28 deficiency is further associated with a decreased lung infiltration by CD8
T lymphocytes. Notably, naive ADAM28-deficient mice already display a drastic reduction of CD8
T cells in spleen which is further observed in lungs. Interestingly,
CD8
T cell characterization revealed that ADAM28-deficiency does not impact proliferation, migration nor activation of CD8
T cells. Our data highlight a functional role of ADAM28 in T cell mobilization and point to an unexpected protective role for host ADAM28 against metastasis.
Membrane-type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF) are two key molecules involved in pericellular proteolysis and cell proliferation during tumor growth ...and angiogenesis. Our previous data showed that MT1-MMP overexpression in human breast carcinoma MCF7 cells induced an up-regulation of VEGF expression. This effect was associated in vivo with accelerated tumor growth and angiogenesis. We now provide evidence that MT1-MMP overexpression specifically affected VEGF-A production and failed to influence that of other VEGF family members (VEGF, B, C, D, or PlGF) or their receptors. The up-regulation of VEGF-A by MT1-MMP was related to an increased transcriptional activation rather than to a modification of mRNA stability. It was blocked by synthetic MMP inhibitors, TIMP2, but not TIMP-1 and abolished by a partial deletion of the catalytic domain or the cytoplasmic tail of MT1-MMP. Analysis of the signal transduction mechanisms demonstrated that MT1-MMP acts through a signaling pathway involving Src tyrosine kinases. Thus, our results provide new insight into the mechanisms of action of MT1-MMP during angiogenesis and suggest that the full enzymatic activity of MT1-MMP is required for a specific up-regulation of VEGF-A through an activation of Src tyrosine kinase pathways.
Membrane‐type 4 matrix metalloprotease (MT4‐MMP) expression in breast adenocarcinoma stimulates tumor growth and metastatic spreading to the lung. However, whether these pro‐tumorigenic and ...pro‐metastatic effects of MT4‐MMP are related to a proteolytic action is not yet known. Through site directed mutagenesis MT4‐MMP has been inactivated in cancer cells through Glutamic acid 249 substitution by Alanine in the active site. Active MT4‐MMP triggered an angiogenic switch at day 7 after tumor implantation and drastically accelerated subcutaneous tumor growth as well as lung colonization in recombination activating gene‐1‐deficient mice. All these effects were abrogated upon MT4‐MMP inactivation. In sharp contrast to most MMPs being primarily of stromal origin, we provide evidence that tumor‐derived MT4‐MMP, but not host‐derived MT4‐MMP contributes to angiogenesis. A genetic approach using MT4‐MMP‐deficient mice revealed that the status of MT4‐MMP produced by host cells did not affect the angiogenic response. Despite of this tumor intrinsic feature, to exert its tumor promoting effect, MT4‐MMP requires a permissive microenvironment. Indeed, tumor‐derived MT4‐MMP failed to circumvent the lack of an host angio‐promoting factor such as plasminogen activator inhibitor‐1. Overall, our study demonstrates the key contribution of MT4‐MMP catalytic activity in the tumor compartment, at the interface with host cells. It identifies MT4‐MMP as a key intrinsic tumor cell determinant that contributes to the elaboration of a permissive microenvironment for metastatic dissemination.
Ten-eleven translocation enzymes (TET1, TET2, and TET3), which induce DNA demethylation and gene regulation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are often ...down-regulated in cancer. We uncover, in basal-like breast cancer (BLBC), genome-wide 5hmC changes related to
regulation. We further demonstrate that
repression is associated with high expression of immune markers and high infiltration by immune cells. We identify in BLBC tissues an anticorrelation between
expression and the major immunoregulator family nuclear factor κB (NF-κB). In vitro and in mice,
is down-regulated in breast cancer cells upon NF-κB activation through binding of p65 to its consensus sequence in the
promoter. We lastly show that these findings extend to other cancer types, including melanoma, lung, and thyroid cancers. Together, our data suggest a novel mode of regulation for
in cancer and highlight a new paradigm in which the immune system can influence cancer cell epigenetics.
In this study, we evaluate the potential involvement of collagenase-3 (MMP13), a matrix metalloproteinase (MMP) family member, in the exudative form of age-related macular degeneration characterized ...by a neovascularisation into the choroid. RT-PCR analysis revealed that human neovascular membranes issued from patients with AMD expressed high levels of Mmp13. The contribution of MMP13 in choroidal neovascularization (CNV) formation was explored by using a murine model of laser-induced CNV and applying it to wild-type mice (WT) and Mmp13-deficient mice (Mmp13 ⁻/⁻ mice). Angiogenic and inflammatory reactions were explored by immunohistochemistry. The implication of bone marrow (BM)-derived cells was determined by BM engraftment into irradiated mice and by injecting mesenchymal stem cells (MSC) isolated from WT BM. The deficiency of Mmp13 impaired CNV formation which was fully restored by WT BM engraftment and partially rescued by several injections of WT MSC. The present study sheds light on a novel function of MMP13 during BM-dependent choroidal vascularization and provides evidence for a role for MSC in the pathogenesis of CNV.
Cancers are complex ecosystems composed of malignant cells embedded in an intricate microenvironment made of different non-transformed cell types and extracellular matrix (ECM) components. The tumor ...microenvironment is governed by constantly evolving cell-cell and cell-ECM interactions, which are now recognized as key actors in the genesis, progression and treatment of cancer lesions. The ECM is composed of a multitude of fibrous proteins, matricellular-associated proteins, and proteoglycans. This complex structure plays critical roles in cancer progression: it functions as the scaffold for tissues organization and provides biochemical and biomechanical signals that regulate key cancer hallmarks including cell growth, survival, migration, differentiation, angiogenesis, and immune response. Cells sense the biochemical and mechanical properties of the ECM through specialized transmembrane receptors that include integrins, discoidin domain receptors, and syndecans. Advanced stages of several carcinomas are characterized by a desmoplastic reaction characterized by an extensive deposition of fibrillar collagens in the microenvironment. This compact network of fibrillar collagens promotes cancer progression and metastasis, and is associated with low survival rates for cancer patients. In this review, we highlight how fibrillar collagens and their corresponding integrin receptors are modulated during cancer progression. We describe how the deposition and alignment of collagen fibers influence the tumor microenvironment and how fibrillar collagen-binding integrins expressed by cancer and stromal cells critically contribute in cancer hallmarks.
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in ...tissue remodeling associated with pathological processes. Among them, ADAMTS12 was identified as an asthma-associated gene in a human genome screening program. However, its functional implication in asthma is not yet documented. The present study aims at investigating potential ADAMTS-12 functions in experimental models of allergic airways disease. Two different in vivo protocols of allergen-induced airways disease were applied to the recently generated Adamts12-deficient mice and corresponding wild-type mice. In this study, we provide evidence for a protective effect of ADAMTS-12 against bronchial inflammation and hyperresponsiveness. In the absence of Adamts12, challenge with different allergens (OVA and house dust mite) led to exacerbated eosinophilic inflammation in the bronchoalveolar lavage fluid and in lung tissue, along with airway dysfunction assessed by increased airway responsiveness following methacholine exposure. Furthermore, mast cell counts and ST2 receptor and IL-33 levels were higher in the lungs of allergen-challenged Adamts12-deficient mice. The present study provides, to our knowledge, the first experimental evidence for a contribution of ADAMTS-12 as a key mediator in airways disease, interfering with immunological processes leading to inflammation and airway hyperresponsiveness.
Neoadjuvant radiotherapy (neoRT) used in cancer treatments aims at improving local tumor control and patient overall survival. The neoRT schedule and the timing of the surgical treatment (ST) are ...empirically based and influenced by the clinician's experience. The current study examines how the sequencing of neoRT and ST affects metastatic dissemination. In a breast carcinoma model, tumors were exposed to different neoRT schedules (2x5Gy or 5x2Gy) followed by surgery at day 4 or 11 post-RT. The impact on the tumor microenvironment and lung metastases was evaluated through immunohistochemical and flow cytometry analyses. After 2x5Gy, early ST (at day 4 post-RT) led to increased size and number of lung metastases as compared to ST performed at day 11. Inversely, after 5x2Gy neoRT, early ST protected the mice against lung metastases. This intriguing relationship between tumor aggressiveness and ST timing could not be explained by differences in classical parameters studied such as hypoxia, vessel density and matrix remodeling. The study of tumor-related inflammation and immunity reveals an increased circulating NK cell percentage following neoRT as compared to non irradiated mice. Then, radiation treatment and surgery were applied to tumor-bearing NOD/SCID mice. In the absence of NK cells, neoRT appears to increase lung metastatic dissemination as compared to non irradiated tumor-bearing mice. Altogether our data demonstrate that the neoRT schedule and the ST timing affect metastasis formation in a pre-clinical model and points out the potential role of NK cells. These findings highlight the importance to cautiously tailor the optimal window for ST following RT.
Among mammary tumor-infiltrating immune cells, the highest expression of podoplanin (PDPN) is found in a subset of tumor-associated macrophages (TAMs). We hereby demonstrate that PDPN is involved in ...the attachment of this TAM subset to lymphatic endothelial cells (LECs). Mechanistically, the binding of PDPN to LEC-derived galectin 8 (GAL8) in a glycosylation-dependent manner promotes the activation of pro-migratory integrin β1. When proximal to lymphatics, PDPN-expressing macrophages (PoEMs) stimulate local matrix remodeling and promote vessel growth and lymphoinvasion. Anti-integrin β1 blockade, macrophage-specific Pdpn knockout, or GAL8 inhibition impairs TAM adhesion to LECs, restraining lymphangiogenesis and reducing lymphatic cancer spread. In breast cancer patients, association of PoEMs with tumor lymphatic vessels correlates with incidences of lymph node and distant organ metastasis.
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