Cancer cachexia alters intracellular surfactant metabolism but not total alveolar surface area
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Dyspnoea is frequently observed in cancer cachectic patients. Little is known whether this is accompanied by structural or functional alterations of the lung. We hypothesized that in analogy to calorie restriction cancer cachexia leads to loss of alveolar surface area and surfactant. Mice were subjected to subcutaneous injection of Lewis lung carcinoma cells (tumour group, TG) or saline (control group, CG). Twenty-one days later blood samples and the lungs were taken. Using design-based stereology, the alveolar surface area and the lamellar body (Lb) content were quantified. Messenger RNA expression of surfactant proteins, ABCA3 and various growth factors was investigated by quantitative RT-PCR. Intraalveolar surfactant subtype composition was analyzed by differential centrifugation. TG mice showed reduced body weight and anaemia but no reduction of lung volume or alveolar surface area. The volume of Lb was significantly reduced and mRNA levels of ABCA3 transporter tended to be lower in TG versus CG. Surfactant protein expression and the ratio between active and inactive intraalveolar surfactant subtypes were not altered in TG. Growth factor mRNA levels were not different between CG and TG lungs but the tumour expressed growth factor mRNA. Vascular endothelial growth factor was significantly enhanced in blood plasma. The present study demonstrates structural alterations of the lung associated with cancer cachexia. These include reduction of Lb content despite normal intraalveolar surfactant and alveolar surface area. The pulmonary phenotype of the cancer cachectic mouse differs from the calorie restricted mouse possibly due to growth factors released from the tumour tissue.
KeywordsCancer cachexia Stereology Electron microscopy Alveolar remodelling Surfactant
The authors are grateful to Petra Hartmann, Gerhard Kripp, Gerd Magdowski, Tamara Papadakis, and Silvia Schauer for expert technical assistance. The authors wish to thank the Verein zur Förderung der Krebsforschung in Gießen e. V. for a research grant (to CM). SKD was funded in part by the FWF grant F30 “Lipotoxicity” project P13 (to GH) and by the PhD program Molecular Medicine of the Medical University of Graz. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
- Besnard V, Matsuzaki Y, Clark J, Xu Y, Wert SE, Ikegami M, Stahlman MT, Weaver TE, Hunt AN, Postle AD, Whitsett JA (2010) Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice. Am J Physiol Lung Cell Mol Physiol 298:L646–L659PubMedCrossRefGoogle Scholar
- Brasch F, Schimanski S, Mühlfeld C, Barlage S, Langmann T, Aslanidis C, Boettcher A, Dada A, Schroten H, Mildenberger E, Prueter E, Ballmann M, Ochs M, Johnen G, Griese M, Schmitz G (2006) Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency. Am J Respir Crit Care Med 174:571–580PubMedCrossRefGoogle Scholar
- Budzynski W (1982) Lewis lung carcinoma in mice as an experimental therapy model. I. The growth kinetics and the effect of tumor on host. Arch Immunol Ther Exp (Warsz) 30:363–372Google Scholar
- Cox DR (1958) Planning of experiments. Wiley, New York, p 158Google Scholar
- Howard CV, Reed MG (2005) Unbiased stereology: three-dimensional measurement in microscopy, 2nd edn. Garland Science/BIOS Scientific, AbingdonGoogle Scholar
- Hsia CC, Hyde DM, Ochs M, Weibel ER, ATS/ERS Joint Task Force on Quantitative Assessment of Lung Structure (2010) An official research policy statement of the American Thoracic Society/European Respiratory Society: standards for quantitative assessment of lung structure. Am J Respir Crit Care Med 181:394–418PubMedCrossRefGoogle Scholar
- Weibel ER (1979) Stereological methods. Practical methods for biological morphometry. Academic Press, LondonGoogle Scholar