The tumor microenvironment and its contribution to tumor evolution toward metastasis

Cancer cells acquire cell-autonomous capacities to undergo limitless proliferation and survival through the activation of oncogenes and inactivation of tumor suppressor genes. Nevertheless, the formation of a clinically relevant tumor requires support from the surrounding normal stroma, also referred to as the tumor microenvironment. Carcinoma-associated fibroblasts, leukocytes, bone marrow-derived cells, blood and lymphatic vascular endothelial cells present within the tumor microenvironment contribute to tumor progression. Recent evidence indicates that the microenvironment provides essential cues to the maintenance of cancer stem cells/cancer initiating cells and to promote the seeding of cancer cells at metastatic sites. Furthermore, inflammatory cells and immunomodulatory mediators present in the tumor microenvironment polarize host immune response toward specific phenotypes impacting tumor progression. A growing number of studies demonstrate a positive correlation between angiogenesis, carcinoma-associated fibroblasts, and inflammatory infiltrating cells and poor outcome, thereby emphasizing the clinical relevance of the tumor microenvironment to aggressive tumor progression. Thus, the dynamic and reciprocal interactions between tumor cells and cells of the tumor microenvironment orchestrate events critical to tumor evolution toward metastasis, and many cellular and molecular elements of the microenvironment are emerging as attractive targets for therapeutic strategie

The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis

Matricellular proteins play multiple roles in primary tumor growth, local invasion and tumor angiogenesis. However, their contribution to metastasis and the putative mechanisms involved are less well characterized. In ER-negative human breast cancer, elevated expression levels of the matricellular protein Cysteine-rich angiogenic inducer 61 (CYR61) are associated with more aggressive progression. Here, we investigated the role of CYR61 in breast cancer lung metastasis using the triple negative human breast cancer cell lines MDA-MB-231 and SUM159. Silencing of CYR61 significantly decreased lung metastasis from tumors orthotopically implanted in pre-irradiated or naive mammary tissue and upon tail vein injection. Constitutive CYR61 silencing impaired cancer cell extravasation to the lung during the first 24 hours after tail vein injection. In contrast, CYR61 inducible silencing starting 24 hours after cancer cell injection had no impact on lung metastasis formation. In vitro experiments revealed that CYR61 silencing decreased cancer cell transendothelial migration and motility, reduced CYR61 levels present at the cell surface and sensitized cancer cells to anoikis. Furthermore, we demonstrate that CYR61-dependent cell survival under non-adhesive conditions relied, at least partially, on β1 integrin ligation and AMPKα signaling while it was independent of AKT, FAK and ERK1/2 activation. Our data provide the first evidence that CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and protecting from anoikis during initial seeding to the lung. The uncovered CYR61-β1 integrin-AMPKα axis may serve as a potential therapeutic target to prevent breast cancer metastasis to the lung

Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target

© 2009 Albini et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer

Neoadjuvant and adjuvant chemotherapies provide survival benefits to breast cancer patients, in particular in estrogen receptor negative (ER-) cancers, by reducing rates of recurrences. It is assumed that the benefits of (neo)adjuvant chemotherapy are due to the killing of disseminated, residual cancer cells, however, there is no formal evidence for it. Here, we provide experimental evidence that ER- breast cancer cells that survived high-dose Doxorubicin and Methotrexate based chemotherapies elicit a state of immunological dormancy. Hallmark of this dormant phenotype is the sustained activation of the IRF7/IFN-beta/IFNAR axis subsisting beyond chemotherapy treatment. Upregulation of IRF7 in treated cancer cells promoted resistance to chemotherapy, reduced cell growth and induced switching of the response from a myeloid derived suppressor cell-dominated immune response to a CD4(+)/CD8(+) T cell-dependent anti-tumor response. IRF7 silencing in tumor cells or systemic blocking of IFNAR reversed the state of dormancy, while spontaneous escape from dormancy was associated with loss of IFN-beta production. Presence of IFN-beta in the circulation of ER- breast cancer patients treated with neoadjuvant Epirubicin chemotherapy correlated with a significantly longer distant metastasis-free survival. These findings establish chemotherapy-induced immunological dormancy in ER- breast cancer as a novel concept for (neo)adjuvant chemotherapy activity, and implicate sustained activation of the IRF7/IFN-beta/IFNAR pathway in this effect. Further, IFN-beta emerges as a potential predictive biomarker and therapeutic molecule to improve outcome of ER- breast cancer patients treated with (neo)adjuvant chemotherapy.Peer reviewe

The role of innate immunity in tumor angiogenesis: identification of downstream mediators in the IL-12 mediated anti-angiogenic activity of Angiostatin.

The numerous studies on Angiostatin (AST) mechanisms of angiogenesis inhibition have focused on the potential receptor-mediated interactions with endothelial cells. Although these studies have provided potential mechanisms, no single receptor system has been definitively shown to mediate AST activity. Recent studies have shown that inflammatory cells, in particular macrophages and neutrophils, are also targets of AST. These cells are part of a network that generates one of the most powerful anti-angiogenic cytokines: interleukin-12 (IL-12). We show that in in vivo preclinical studies, IL-12 is an essential mediator of AST antiangiogenic activity. Function blocking antibodies to IL-12 revert angiogenesis inhibition induced by AST. Further, AST is unable to exert angiogenesis inhibition in mice with gene targeted deletions of the IL-12 receptor IL-12R2, specific for IL-12, or in mice gene targeted for the IL- 12 p40 subunit. However, AST retains anti-angiogenic activity in IFNgene targeted mice, suggesting an IFNindependent angiogenesis inhibition mechanism as previously observed. We also identified a short synthetic peptide localized to the lysine binding domain that completely reproduces the IL-12 dependent anti-angiogenic properties of AST. Since endothelial cells do not express the IL-12 receptor, nor do they essentially change gene expression patterns when treated with AST in vitro, our data show that the immune system forms an integral part of the anti-angiogenic effects of AST, by both responding to AST and providing downstream signals to the endothelium. AST induced IL-12 synthesis by human macrophages polarized toward M1 phenotype in vitro. We also identified a short synthetic peptide with potential application in oncological therapy, that reproduced the IL-12 dependent anti-angiogenic properties of angiostatin

The role of innate immunity in tumor angiogenesis: identification of downstream mediators in the IL-12 mediated anti-angiogenic activity of Angiostatin.

The numerous studies on Angiostatin (AST) mechanisms of angiogenesis inhibition have focused on the potential receptor-mediated interactions with endothelial cells. Although these studies have provided potential mechanisms, no single receptor system has been definitively shown to mediate AST activity. Recent studies have shown that inflammatory cells, in particular macrophages and neutrophils, are also targets of AST. These cells are part of a network that generates one of the most powerful anti-angiogenic cytokines: interleukin-12 (IL-12). We show that in in vivo preclinical studies, IL-12 is an essential mediator of AST antiangiogenic activity. Function blocking antibodies to IL-12 revert angiogenesis inhibition induced by AST. Further, AST is unable to exert angiogenesis inhibition in mice with gene targeted deletions of the IL-12 receptor IL-12R\uf0622, specific for IL-12, or in mice gene targeted for the IL- 12 p40 subunit. However, AST retains anti-angiogenic activity in IFN\uf067\uf020gene targeted mice, suggesting an IFN\uf067\uf020independent angiogenesis inhibition mechanism as previously observed. We also identified a short synthetic peptide localized to the lysine binding domain that completely reproduces the IL-12 dependent anti-angiogenic properties of AST. Since endothelial cells do not express the IL-12 receptor, nor do they essentially change gene expression patterns when treated with AST in vitro, our data show that the immune system forms an integral part of the anti-angiogenic effects of AST, by both responding to AST and providing downstream signals to the endothelium. AST induced IL-12 synthesis by human macrophages polarized toward M1 phenotype in vitro. We also identified a short synthetic peptide with potential application in oncological therapy, that reproduced the IL-12 dependent anti-angiogenic properties of angiostatin

The role of innate immunity in tumor angiogenesis: identification of downstream mediators in the IL-12 mediated anti-angiogenic activity of Angiostatin.

The numerous studies on Angiostatin (AST) mechanisms of angiogenesis inhibition have focused on the potential receptor-mediated interactions with endothelial cells. Although these studies have provided potential mechanisms, no single receptor system has been definitively shown to mediate AST activity. Recent studies have shown that inflammatory cells, in particular macrophages and neutrophils, are also targets of AST. These cells are part of a network that generates one of the most powerful anti-angiogenic cytokines: interleukin-12 (IL-12). We show that in in vivo preclinical studies, IL-12 is an essential mediator of AST antiangiogenic activity. Function blocking antibodies to IL-12 revert angiogenesis inhibition induced by AST. Further, AST is unable to exert angiogenesis inhibition in mice with gene targeted deletions of the IL-12 receptor IL-12R2, specific for IL-12, or in mice gene targeted for the IL- 12 p40 subunit. However, AST retains anti-angiogenic activity in IFNgene targeted mice, suggesting an IFNindependent angiogenesis inhibition mechanism as previously observed. We also identified a short synthetic peptide localized to the lysine binding domain that completely reproduces the IL-12 dependent anti-angiogenic properties of AST. Since endothelial cells do not express the IL-12 receptor, nor do they essentially change gene expression patterns when treated with AST in vitro, our data show that the immune system forms an integral part of the anti-angiogenic effects of AST, by both responding to AST and providing downstream signals to the endothelium. AST induced IL-12 synthesis by human macrophages polarized toward M1 phenotype in vitro. We also identified a short synthetic peptide with potential application in oncological therapy, that reproduced the IL-12 dependent anti-angiogenic properties of angiostatin

Innate immune cells and their contribution to T-cell-based immunotherapy

In recent years, immunotherapy has become the most promising therapy for a variety of cancer types. The development of immune checkpoint blockade (ICB) therapies, the adoptive transfer of tumor-specific T cells (adoptive cell therapy (ACT)) or the generation of T cells engineered with chimeric antigen receptors (CAR) have been successfully applied to elicit durable immunological responses in cancer patients. However, not all the patients respond to these therapies, leaving a consistent gap of therapeutic improvement that still needs to be filled. The innate immune components of the tumor microenvironment play a pivotal role in the activation and modulation of the adaptive immune response against the tumor. Indeed, several efforts are made to develop strategies aimed to harness innate immune cells in the context of cancer immunotherapy. In this review, we describe the contribution of innate immune cells in T-cell-based cancer immunotherapy and the therapeutic approaches implemented to broaden the efficacy of these therapies in cancer patients