Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention.

Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm

Mononuclear phagocyte plasticity includes the expression of functions related to the resolution of inflammation, tissue repair and remodelling, particularly when these cells are set in an M2 or an M2-like activation mode. Macrophages are credited with an essential role in remodelling during ontogenesis. In extraembryonic life, under homeostatic conditions, the macrophage trophic and remodelling functions are recapitulated in tissues such as bone, mammary gland, decidua and placenta. In pathology, macrophages are key components of tissue repair and remodelling that occur during wound healing, allergy, parasite infection and cancer. Interaction with cells bearing stem or progenitor cell properties is likely an important component of the role of macrophages in repair and remodelling. These properties of cells of the monocyte-macrophage lineage may represent a tool and a target for therapeutic exploitation.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.4133

Macrophage plasticity and polarization in tissue repair and remodelling.

Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.

/pdf/four-faces-of-cellular-senescence-3pru9zecyf.pdf

Four faces of cellular senescence

Glioblastoma multiforme (GBM) comprises several molecular subtypes, including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend on colony stimulating factor-1 (CSF-1) for differentiation and survival. We used an inhibitor of the CSF-1 receptor (CSF-1R) to target TAMs in a mouse proneural GBM model, which significantly increased survival and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma-secreted factors, including granulocyte-macrophage CSF (GM-CSF) and interferon-γ (IFN-γ), facilitated TAM survival in the context of CSF-1R inhibition. Expression of alternatively activated M2 markers decreased in surviving TAMs, which is consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in patients with proneural GBM. Our results identify TAMs as a promising therapeutic target for proneural gliomas and establish the translational potential of CSF-1R inhibition for GBM.

/pdf/csf-1r-inhibition-alters-macrophage-polarization-and-blocks-4wzzyc5sc6.pdf

CSF-1R inhibition alters macrophage polarization and blocks glioma progression

As angiogenesis is essential for tumor growth and metastasis, controlling tumor-associated angiogenesis is a promising tactic in limiting cancer progression. The tumor microenvironment comprises numerous signaling molecules and pathways that influence the angiogenic response. Understanding how these components functionally interact as angiogenic stimuli or as repressors and how mechanisms of resistance arise is required for the identification of new therapeutic strategies. Achieving a durable and efficient antiangiogenic response will require approaches to simultaneously or sequentially target multiple aspects of the tumor microenvironment.

Tumor angiogenesis: molecular pathways and therapeutic targets

The microenvironment of solid tumors is characterized by a reactive stroma with an abundance of inflammatory mediators and leukocytes, dysregulated vessels and proteolytic enzymes TAM, major players in the connection between inflammation and cancer, summarize a number of functions (eg, promotion of tumor cell proliferation and angiogenesis, incessant matrix turnover, repression of adaptive immunity), which ultimately have an important impact on disease progression Thus, together with other myeloid-related cells present at the tumor site (Tie2 macrophages and MDSCs), TAM represent an attractive target of novel biological therapies of tumors

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.0609385

Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation

The link between inflammation and cancer proposed more than a century ago by Rudolf Virchow, who noticed the infiltration of leukocytes in malignant tissues, has recently found a number of genetic and molecular confirmations. Experimental, clinical and epidemiological studies have revealed that chronic inflammation contributes to cancer progression and even predisposes to different types of cancer. Cancer-associated inflammation includes: the presence of leukocyte infiltration; the expression of cytokines such as tumor necrosis factor (TNF) or interleukin (IL)-1; chemokines such as CCL2 and CXCL8; active tissue remodelling and neo-angiogenesis. Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. Many observations indicate that, in the tumor micro-environment, TAM have several protumoral functions, including expression of growth factors, matrix proteases, promotion of angiogenesis and suppression of adaptive immunity. In this review we will discuss the role of TAM in the inflammatory micro-environment of solid tumors and will try to identify potential target for future therapeutic approaches.

The inflammatory micro-environment in tumor progression: The role of tumor-associated macrophages

Tumor-associated macrophages (TAMs) are key orchestrators of the tumor microenvironment directly affecting neoplastic cell growth, neoangiogenesis, and extracellular matrix remodeling. In turn, the tumor milieu strongly influences maturation of TAMs and shapes several of their features. To address the early macrophage (M) differentiation phase in a malignant context, we mimicked a tumor microenvironment by in vitro coculturing human blood monocytes with conditioned media from different cancer cell lines. Only 2 out of 16 tumor cell lines induced M differentiation due to secreted M-CSF isoforms, including high molecular mass species. A global gene profiling of tumor-conditioned M was performed. Comparison with other datasets (polarized M1-M, M2-M, and TAMs isolated from human tumors) highlighted the upregulation of several genes also shared by TAM and M2-polarized M. The most expressed genes were selenoprotein 1, osteoactivin, osteopontin, and, interestingly, migration-stimulating factor (MSF), a poorly studied oncofoetal isoform of fibronectin. MSF (present in fetal/cancer epithelial and stromal cells but not in healthy tissues) was never identified in M. MSF production was confirmed by immunohistochemistry in human TAMs. MSF was induced by M-CSF, IL-4, and TGFbeta but not by proinflammatory stimuli. RNA and protein analysis clearly demonstrated that it is specifically associated with the M2 polarization of M. Tumor-conditioned M-derived MSFs strongly stimulated tumor cell migration, thus contributing to the motile phenotype of neoplastic cells. In conclusion, MSF is a new molecule associated with the M2 polarization of M and expressed by TAMs. Its biological function may contribute to M-mediated promotion of cancer cell invasion and metastasis.

Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility

The microenvironment of solid tumors is characterized by a reactive stroma with an abundance of inflammatory mediators and leukocytes, dysregulated vessels and proteolytic enzymes. TAM, major players in the connection between inflammation and cancer, summarize a number of functions (e.g., promotion of tumor cell proliferation and angiogenesis, incessant matrix turnover, repression of adaptive immunity), which ultimately have an important impact on disease progression. Thus, together with other myeloid-related cells present at the tumor site (Tie2 macrophages and MDSCs), TAM represent an attractive target of novel biological therapies of tumors.

Tumor-Associated Macrophages (TAM) as Major Players of the Cancer-Related Inflammation

Inflammation has been suggested to represent the seventh hallmark of cancer. Myelomonocytic cells are a key component of cancer-related inflammation. Tumor-associated macrophages and their mediators affect key elements in the multistep process of invasion and metastasis, from interaction with the extracellular matrix to the construction of a pre-metastatic niche. Evidence indicating that inflammatory mediators affect genetic stability and cause persistent epigenetic alterations suggests that inflammatory components of the tumor microenvironment impacts on fundamental mechanisms responsible for the generation of metastatic variants. These results provide impetus for efforts aimed at translating cancer-related inflammation into diagnostic–prognostic markers and innovative therapeutic strategies.

Graziella Solinas

Papers

Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation

The inflammatory micro-environment in tumor progression: The role of tumor-associated macrophages

Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility

Tumor-Associated Macrophages (TAM) as Major Players of the Cancer-Related Inflammation

Inflammation-mediated promotion of invasion and metastasis