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  • br Introduction Analyses of genomic alterations in cancer ha

    2019-11-08


    Introduction Analyses of genomic alterations in cancer have identified epidermal growth factor receptor (EGFR) as one of the most potent “oncogenic driver” kinases that is present in many epithelial tumors including endometrial, breast, prostate, skin, esophagus, lung, stomach, colorectal, and renal cancer [1]. Furthermore, high expression levels of EGFR and/or corresponding ligands have been reported for a number of tumor types [2]. EGFR has therefore been regarded as a rational target for anti-tumor therapy initiating clinical studies for various types of cancer, including lung, pancreatic, colorectal, head and neck cancer and breast cancer [3, 4]. However, the example of lung cancer shows that EGFR-targeted therapies, as single agent, are of limited success with median progression-free survival time prolonged less than one year as compared to chemotherapy [3]. Signaling pathways that bypass the requirement of the targeted oncoprotein for cell survival and proliferation are among the known mechanisms of resistance [3]. Aberrant expression of colony-stimulating factor (CSF)-1receptor (CSF-1R), which plays a key role in the differentiation and maintenance of phagocytic 6-Aminonicotinamide in the healthy adult organism, has been described for epithelial cancer cells from tumors of the female reproductive system [[5], [6], [7], [8]], prostate cancer [9], renal clear cell carcinoma [10], lung [11], colon [12] and gastric cancer [13]. Furthermore, expression of CSF-1R and its ligand have been associated with adverse prognostic outcome in breast, ovarian, endometrial, colon and gastric cancer [6, [13], [14], [15], [16]]. Studies using mainly breast cancer models have demonstrated that CSF-1R contributes to tumor invasiveness [11, [17], [18], [19], [20]]. However, the role of CSF-1R in tumor growth is not well characterized, and the question whether CSF-1R may influence targeted therapies has not yet been addressed. Investigations whether CSF-1R promotes proliferation of the lung cancer cell line A549 have produced inconsistent results [21, 22]. Studies with human breast cancer cell lines SK-BR-3 and MDA-MB-468 suggest that CSF-1R supports proliferation [23], whereas in breast cancer cell lines of a subtype with low expression of luminal differentiation markers (“claudin-low”), CSF-1R reduces proliferation in favor of invasiveness [17]. In a gastric cancer cell line, CSF-1R promotes proliferation and migration [13]. Furthermore, a mouse model with overexpression of CSF-1R in mammary epithelium revealed that CSF-1R induced preneoplastic alterations by increased cellular proliferation in young mice [24]. Yet, mammary tumor formation occurred only in older animals and with low tumor burden. Notably, treatment with a mutagen accelerated tumor development, suggesting that CSF-1R promotes tumor formation on the background of additional tumorigenic alterations. CSF-1R may therefore rather function as a fine tuner of tumorigenesis in the context of other oncogenic alterations in epithelial tumors.
    Materials and methods
    Results
    Discussion Growing knowledge of cancer genomes, epigenomes and biology led to the comprehension that, in most cases, a combination of alterations is required for tumorigenesis. While some tumor promoting alterations are frequently found, and the corresponding genes have been identified as “oncogenic drivers”, the contribution of others is less obvious and/or may be revealed only under certain conditions. Several lines of evidence, mainly derived from breast cancer, support a role for aberrantly expressed CSF-1R as tumorigenesis promoting factor in epithelial derived cancer. However, models for CSF-1R-mediated invasiveness [[17], [18], [19]], BT-20 and MDA-MB-231 cells, carry an EGFR gene amplification [45] and activating mutations in KRAS and BRAF [46, 47], respectively. Proliferation models [23], SK-BR-3 and MDA-MB-468, contain gene amplifications, and correspondingly elevated levels of ErbB2 and EGFR [45, 48], respectively, that drive proliferation of these cells [49, 50], suggesting that aberrantly expressed CSF-1R is one of a number of alterations that contribute collectively to tumorigenesis. Furthermore, CSF-1R is probably rather a fine tuner than a prominent oncogene. However, even a minor contributor may gain significance in cases where the prominent oncogene is suppressed by targeted therapies. Using A431 cells, we show that ectopic expression of CSF-1R does not change cell proliferation as long as oncogenic EGFR is active, but provides a significant growth advantage when EGFR is inhibited by gefitinib.