Myeloid cells in tumor tissues constitute a dynamic immune population characterized by a non-uniform phenotype and diverse functional activities. Both tumor-associated macrophages (TAMs), which are ...more abundantly represented, and tumor-associated neutrophils (TANs) are known to sustain tumor cell growth and invasion, support neoangiogenesis and suppress anticancer adaptive immune responses. In recent decades, several therapeutic approaches have been implemented in preclinical cancer models to neutralize the tumor-promoting roles of both TAMs and TANs. Some of the most successful strategies have now reached the clinic and are being investigated in clinical trials. In this review, we provide an overview of the recent literature on the ever-growing complexity of the biology of TAMs and TANs and the development of the most promising approaches to target these populations therapeutically in cancer patients.
Myeloid cells infiltrating tumors are gaining ever growing attention in the last years because their pro-tumor and immunosuppressive functions are relevant for disease progression and therapeutic ...responses. The functional ambiguity of tumor-associated macrophages (TAMs), mostly promoting tumor evolution, is a challenging hurdle. This is even more evident in the case of cancer stem cells (CSCs); as active participants in the specialized environment of the cancer stem cell niche, TAMs initiate a reciprocal conversation with CSCs. TAMs contribute to protect CSCs from the hostile environment (exogenous insults, toxic compounds, attacks from the immune cells), and produce several biologically active mediators that modulate crucial developmental pathways that sustain cancer cell stemness. In this review, we have focused our attention on the interaction between TAMs and CSCs; we describe how TAMs impact on CSC biology and, in turn, how CSCs exploit the tissue trophic activity of macrophages to survive and progress. Since CSCs are responsible for therapy resistance and tumor recurrence, they are important therapeutic targets. In view of the recent success in oncology obtained by stimulating the immune system, we discuss some macrophage-targeted therapeutic strategies that may also affect the CSCs and interrupt their malevolent alliance.
Inflammation is now a well-recognized hallmark of cancer progression. Tumor-associated macrophages (TAMs) are one of the major inflammatory cells that infiltrate murine and human tumors. While ...epidemiological studies indicate a clear correlation between TAM density and poor prognosis in a number of human cancers, transgenic studies and transcriptome profiling of TAMs in mice have established their crucial role in cancer progression. In fact, TAMs affect diverse aspects of cancer progression including tumor cell growth and survival, invasion, metastasis, angiogenesis, inflammation, and immunoregulation. New evidences have extended the repertoire of these cells to other tumor promoting activities like interactions with cancer stem cells, response to chemotherapy, and tumor relapse. These findings have triggered efforts to target TAMs and their associated molecules to modulate tumor progression. In particular, “re-education” to activate their anti-tumor potential or elimination of tumor promoting TAMs are strategies undergoing preclinical and clinical evaluation. Proof-of-principle studies indicate that TAM-centered therapeutic strategies may contribute to cancer therapy.
An intrinsic (oncogene-driven) pathway and an extrinsic (microenvironment-driven) pathway connect inflammatory reactions and cancer. M2-polarized tumor-associated macrophages and the related ...myeloid-derived suppressor cells are key prototypic components of smoldering inflammation driving neoplastic progression. However, mononuclear phagocytes can exert anti-tumor activity by killing tumor cells and eliciting tissue disruptive reactions (M1), a likely scenario in the early phases of carcinogenesis of immunogenic tumors and following therapeutic intervention. Shifting the macrophage balance represents a viable therapeutic target. Herein, the 'macrophage balance' is discussed in the context of the apparent paradox of tumor promotion by innate immunity-driven inflammation and the seemingly opposed tumor surveillance by adaptive immune responses.
Abstract Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. In the tumor microenvironment neoplastic cells shape the differentiation and functional ...orientation of TAM which, in turn, express several protumoral functions, including secretion of growth factors and matrix-proteases, promotion of angiogenesis and suppression of adaptive immunity. This review analyzes our current knowledge of TAM and their involvement in tumor development and progression. The interplay between TAM and neoplastic cells represents a promising target of future therapeutic approaches.
Myeloid cells infiltrating the tumor microenvironment, especially tumor-associated macrophages (TAMs), are essential providers of cancer-related inflammation, a condition known to accelerate tumor ...progression and limit the response to anti-tumor therapies. As a matter of fact, TAMs may have a dual role while interfering with cancer treatments, as they can either promote or impair their functionality. Here we review the connection between macrophages and anticancer therapies; moreover, we provide an overview of the different strategies to target or re-program TAMs for therapeutic purposes.
Established evidence demonstrates that tumor-infiltrating myeloid cells promote rather than stop-cancer progression. Tumor-associated macrophages (TAMs) are abundantly present at tumor sites, and ...here they support cancer proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Their pro-tumor activities hamper the response of cancer patients to conventional therapies, such as chemotherapy or radiotherapy, and also to immunotherapies based on checkpoint inhibition. Active research frontlines of the last years have investigated novel therapeutic strategies aimed at depleting TAMs and/or at reprogramming their tumor-promoting effects, with the goal of re-establishing a favorable immunological anti-tumor response within the tumor tissue. In recent years, numerous clinical trials have included pharmacological strategies to target TAMs alone or in combination with other therapies. This review summarizes the past and current knowledge available on experimental tumor models and human clinical studies targeting TAMs for cancer treatment.
Abstract 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.
Abstract Invasion and metastasis are key components of cancer progression. Inflammatory mediators, including cytokines and chemokines, can facilitate tumor dissemination. A distinct and largely ...forgotten path is perineural invasion (PNI), defined as the presence of cancer cells in the perinerium space. PNI is frequently used by many human carcinomas, in particular by pancreas and prostate cancer, and is associated with tumor recurrence and pain in advanced patients. Neurotrophic factors have been identified as molecular determinants of PNI. A role for chemokines in this process has been proposed; the chemokine CX3CL1/Fractalkine attracts receptor positive pancreatic tumor cells to disseminate along peripheral nerves. Better understanding of the neurotropism of malignant cells and of the clinical significance of PNI would help the design of innovative strategies for the control of tumor dissemination and pain in cancer patients.
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