Tumor-associated macrophages (TAMs) are important tumor-promoting cells in the breast tumor microenvironment. Preclinically TAMs stimulate breast tumor progression, including tumor cell growth, invasion and metastasis. TAMs also induce resistance to multiple types of treatment in breast cancer models. The underlying mechanisms include: induction and maintenance of tumor-promoting phenotype in TAMs, inhibition of CD8+ T cell function, degradation of extracellular matrix, stimulation of angiogenesis and inhibition of phagocytosis. Several studies reported that high TAM infiltration of breast tumors is correlated with a worse patient prognosis. Based on these findings, macrophage-targeted treatment strategies have been developed and are currently being evaluated in clinical breast cancer trials. These strategies include: inhibition of macrophage recruitment, repolarization of TAMs to an antitumor phenotype, and enhancement of macrophage-mediated tumor cell killing or phagocytosis. This review summarizes the functional aspects of TAMs and the rationale and current evidence for TAMs as a therapeutic target in breast cancer.

BackgroundOnly a minority of cancer patients benefits from the combination of EGFR-inhibition and radiotherapy in head and neck squamous cell carcinoma (HNSCC). A potential resistance mechanism is activation of EGFR and/or downstream pathways by stimuli in the microenvironment. The aim of this study was to find molecular targets induced by the microenvironment by determining the in vitro and in vivo expression of proteins of the EGFR-signaling network in 6 HNSCC lines. As hypoxia is an important microenvironmental parameter associated with poor outcome in solid tumors after radiotherapy, we investigated the relationship with hypoxia in vitro and in vivo.MethodsSix human HNSCC cell lines were both cultured as cell lines (in vitro) and grown as xenograft tumors (in vivo). Expression levels were determined via western blot analysis and localization of markers was assessed via immunofluorescent staining. To determine the effect of hypoxia and pAKT-inhibition on cell survival, cells were incubated at 0.5% O2 and treated with MK-2206.ResultsWe observed strong in vitro-in vivo correlations for EGFR, pEGFR and HER2 (rs=0.77, p=0.10, rs=0.89, p=0.03) and rs=0.93, p=0.02, respectively), but not for pAKT, pERK1/2 or pSTAT3 (all rs<0.55 and p>0.30). In vivo, pAKT expression was present in hypoxic cells and pAKT and hypoxia were significantly correlated (rs=0.51, p=0.04). We confirmed in vitro that hypoxia induces activation of AKT. Further, pAKT-inhibition via MK-2206 caused a significant decrease in survival in hypoxic cells (p<0.01), but not in normoxic cells.ConclusionsThese data suggest that (p)EGFR and HER2 expression is mostly determined by intrinsic features of the tumor cell, while the activation of downstream kinases is highly influenced by the tumor microenvironment. We show that hypoxia induces activation of AKT both in vitro and in vivo, and that hypoxic cells can be specifically targeted by pAKT-inhibition. Targeting pAKT is thus a potential way to overcome therapy resistance induced by hypoxia and improve patient outcome.

Development of new oncology drugs has increased since the improved understanding of cancer's complex biology. The oncology field has become the top therapeutic research area for new drugs. However, only a limited number of drugs entering clinical trials will be approved for use as the standard of care for cancer patients. Molecular imaging is increasingly perceived as a tool to support go/no-go decisions early during drug development. It encompasses a wide range of techniques that include radiolabeling a compound of interest followed by visualization with SPECT or PET. Radiolabeling can be performed using a variety of radionuclides, which are preferably matched to the compound on the basis of size and half-life. Imaging can provide information on drug behavior in vivo, whole-body drug target visualization, and heterogeneity in drug target expression. This review focuses on current applications of molecular imaging in the development of small molecules, antibodies, and antihormonal anticancer drugs.