Macrophage migration and gene expression in response to tumor hypoxia

Abstract

Monocytes are recruited into tumors from the circulation along defined chemotactic gradients and they then differentiate into tumor-associated macrophages (TAMs). Recent evidence has shown that large numbers of TAMs are attracted to and retained in avascular and necrotic areas, where they are exposed to tumor hypoxia. At these sites, TAMs appear to undergo marked phenotypic changes with activation of hypoxia-inducible transcription factors, dramatically upregulating the expression of a large number of genes encoding mitogenic, proangiogenic and prometastatic cytokines and enzymes. As a consequence, high TAMs density has been correlated with increased tumor growth and angiogenesis in various tumor types. Since hypoxia is a hallmark feature of malignant tumors and hypoxic tumor cells are relatively resistant to radio-and chemotherapy, these areas have become a target for novel forms of anticancer therapy. These include hypoxiatargeted gene therapy in which macrophages are armed with therapeutic genes that are activated by hypoxia-responsive promoter elements. This restricts transgene expression to hypoxic areas, where the gene product is then released and acts on neighboring hypoxic tumor cells or proliferating blood vessels. In this way, the responses of macrophages to tumor hypoxia can be exploited to deliver potent antitumor agents to these poorly vascularized, and thus largely inaccessible, areas of tumors. ' 2005 Wiley-Liss, Inc.

Normalization of the Ovarian Cancer Microenvironment by SPARC

“…69, 70). As a consequence, tumor-associated monocytes/macrophages undergo marked phenotypic changes with activation of hypoxiainducible factor 1a, dramatically up-regulating the expression of a large number of genes encoding mitogenic, proangiogenic, and prometastatic cytokines, enzymes, and bioactive lipids (70,71). Interestingly, in vivo and in vitro studies have shown that VEGF, MMPs, and IL-6 in the tumor microenvironment inhibit the differentiation and maturation of dendritic cells and switch their differentiation toward the macrophage lineage (72,73).…”

Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation

“…In contrast, classically activated M1-like TAMs secrete immunostimulatory cytokines that have direct tumoricidal activity. M1-like TAMs, however, are sparse and confined to the less hypoxic regions of tumors (15). The presence of M2-like TAMs in tumors correlates with poor prognosis (16,17), whereas the presence of M1-like TAMs correlates with longer survival for patients (18).…”

Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer

“…Cancer cells release chemo-attractive factors, such as MCP-1 (monocyte chemotactic protien-1) and RANTES (regulated upon activation, normal T-cell expressed and secreted), and actively recruit leukocytes to tumors [10,11]. Once the bone marrow derived-cells (BMDC) arrive at the tumor site, they contribute to angiogenesis and tumor progression by expressing pro-angiogenic growth factors such as IL-1, VEGF, and IL-8 [7,12].…”