Pneumologie 2012; 66 - A609
DOI: 10.1055/s-0032-1315532

The effect of endotoxin on cell-proliferation and responsiveness to treatment in Non-small-cell-lung-cancer

E Schütz 1, D Baier 1, F Kamlah 2, R Savai 1, A Schmall 1, G Dahlem 1, U Grandel 1, U Sibelius 1, W Seeger 3, F Grimminger 1, K Hattar 1
  • 1Medical Clinic IV/V, Department of Internal Medicine, UGMLC, University of Gießen
  • 2Clinic for Radiotherapy and Radiooncology, UGMCL, Philipps-University Marburg
  • 3Medical Clinic II, Department of Internal Medicine, UGMLC, University of Gießen

Pulmonary infections are common complications in patients with lung cancer and worsen prognosis. The most common pathogens found in patients with lung cancer are gram-negative bacteria whose virulence is caused by the components of the cell wall, especially by gram-negative LPS. For this reason we analysed, if endotoxin would activate cell-proliferation and moreover we wanted to know if sensitivity to radio- and chemotherapy, is modified by endotoxin.

Three human non small cell lung cancer (NSCLC) cell lines, A549 (adenocarcinoma), H23 (adenocarcinoma) and H226 (squamous epithelium carcinoma) were incubated with different concentrations of LPS, rising from 0.1µg/ml to 10µg/ml. Cell-proliferation was quantified by cell counting, moreover, we investigated clonogenic survival (Colony Assay) of native and of irradiated cells with a dose of 2 and 6Gy.

Relating to each cell-line on non-irradiated, native cells the effect of LPS resulted in an increase both of cell-proliferation and clonogenic survival. Radiotherapy induced in all cell-lines a significant reduction of clonogenic survival and it was obvious that the H23-adenocarcinoma has been the most radiosensitive line. In all cells incubated with endotoxin the radiation effect has been reduced by 50%, which means that the clonogenic survival increased after LPS treatment. Thus, sensitivity to irradiation was severely blunted in the presence of endotoxin in a dose-dependent manner, with 1–10µg/ml of endotoxin being the most effective concentration In parallel the radiation- related reduction of the cell number of was increased by LPS.

Interestingly also the sensitivity towards cisplatin-based cytostatic therapy was weakened in LPS-incubated A549-adenocarcinoma-cells. LPS treatment resulted in a resistance to cisplatin-based chemotherapy, as measured by increased BrdU and metabolic activity of LPS-stimulated and cisplatin-incubated A549-cells. Moreover the multidrug-restistance proteins (MDR)ABCB1 (=MDR1) and ABCG2 have been upregulated in LPS-stimulated cells.

Summary:

In NSCLC-cells LPS induces not only growth but also a decreased sensitivity towards radio- and chemotherapy. One underlying mechanism may be the upregulation of MDR-proteins. Our results give a hint that bacterial infections may not be a simple epiphenomen but are actively involved in the progression of lung cancer by directly promoting tumor growth and by inducing therapy resistance.