Macrophage IGF 1 may thus have a pathological role in lung cancer. Direct connections between lung macrophages selleck inhibitor and AC progression in vivo are less clear than the well described interactions between macrophages and breast cancer cells, or osteoclasts and oncolytic breast cancer metastases. Lung tumor cells Inhibitors,Modulators,Libraries over expres sing Inhibitors,Modulators,Libraries IL 1b enhanced macrophage recruitment Inhibitors,Modulators,Libraries and tumor angiogenesis when implanted into syngeneic mice. In our studies, BALF CSF 1 levels were nearly undetectable while IL 1b levels were significantly higher in tumor bearing lungs vs. na ve. How ever, recombinant IL 1b did not affect the proliferation of neoplastic lung epithelial cells in vitro, either alone or in combination with IGF 1. IL 1b also did not signifi cantly affect IGF 1 production by MH S macrophages.
Although not responsible for the macrophage induced neoplastic proliferation observed in our studies, IL 1b stimulated macrophages produce more pro angiogenic factors, and this interleukin may contribute to the increased numbers of macrophages in tumor bearing lungs. In lung cancer therapy, anti angiogenic or anti inflam matory agents show widespread efficacy across Inhibitors,Modulators,Libraries many cancer types, while inhibition of the EGF receptor is mainly effective in the NSCLC sub population containing activating EGFR mutations. EGFR mutant lung cancers eventually become resistant to anti EGFR therapies, and then progress rapidly. One proposed mechanism for lung cancer resistance to anti EGFR therapy is the increased expression of other EGFR family receptors and/or the Inhibitors,Modulators,Libraries IGF 1 receptor.
Similar to the well described hetero 17-DMAG hsp90 dimerization among the EGF receptor family, IGF 1R can form functional complexes with EGFR. Unlike IGF 1R, EGFR can be stimulated by numerous EGF like factors, which macrophages produce in a tissue and disease specific manner. However, we show that 1) BALF EGF levels are very low and do not differ between na ve and tumor bearing lungs. 2) macrophages produce trace amounts of EGF in vitro. and 3) EGF does not stimulate neoplastic lung proliferation either alone or in combina tion with IGF 1 or M CM. Combined, these observations indicate that EGF is not involved in the macrophage stimulation of pul monary epithelial growth in vitro, and argue against sig nificant lung macrophage EGF production in vivo. The increased EGFR phosphorylation in primary mouse lung tumors bearing Kras mutations that we previously reported could result from IGF 1R/EGFR coupling and trans activation after IGF 1 stimulation. Muta tions in EGFR and KRAS are mutually exclusive in both human and murine NSCLC, and EGF stimulation would not be expected drive Kras mutant models of lung can cer.