Anti-LIFR monoclonal antibody, clone N99012522

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology(1,2). The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance(3-7). Furthermore, PSC activation occurs very early during PDAC tumorigenesis(8-10), and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.

Ciliary neurotrophic factor (CNTF) has been implicated in the survival and regeneration of adult rat retinal ganglion cells (RGCs). Expression of CNTF and its receptors, ciliary neurotrophic factor receptor alpha (CNTFRalpha) and leukemia inhibitory factor receptor (LIFR) was studied in normal, 6-h, 1-, and 3-day optic nerve transected retinas. Optic nerve transection was performed on the right eye in one group. In the other group, it was performed 5 days after intratectal Fluorogold injection. Retinas were studied using immunohistochemical labeling and Western blot analysis. Astrocytes were labeled with GFAP and Muller cells with glutamine synthetase. CNTF was observed in identifiable astrocytes and Muller cells, and its intensity increased in the experimental retinas. CNTFRalpha was localized on RGCs in experimental retinas. LIFR was localized on RGCs and Miller cells in normal and experimental retinas. CNTF and its receptors are differentially expressed after optic nerve transection and could help delay RGC death in such a stressful environment. (C) 2004 Elsevier B.V. All rights reserved.