Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse

Abstract

BackgroundThe majority of cancer patients experience dramatic weight loss, due to cachexia and consisting of skeletal muscle and fat tissue wasting. Cachexia is a negative prognostic factor, interferes with therapy and worsens the patients' quality of life by affecting muscle function. Mice bearing ectopically-implanted C26 colon carcinoma are widely used as an experimental model of cancer cachexia. As part of the search for novel clinical and basic research applications for this experimental model, we characterized novel cellular and molecular features of C26-bearing mice.MethodsA fragment of C26 tumor was subcutaneously grafted in isogenic BALB/c mice. The mass growth and proliferation rate of the tumor were analyzed. Histological and cytofluorometric analyses were used to assess cell death, ploidy and differentiation of the tumor cells. The main features of skeletal muscle atrophy, which were highlighted by immunohistochemical and electron microscopy analyses, correlated with biochemical alterations. Muscle force and resistance to fatigue were measured and analyzed as major functional deficits of the cachectic musculature.ResultsWe found that the C26 tumor, ectopically implanted in mice, is an undifferentiated carcinoma, which should be referred to as such and not as adenocarcinoma, a common misconception. The C26 tumor displays aneuploidy and histological features typical of transformed cells, incorporates BrdU and induces severe weight loss in the host, which is largely caused by muscle wasting. The latter appears to be due to proteasome-mediated protein degradation, which disrupts the sarcomeric structure and muscle fiber-extracellular matrix interactions. A pivotal functional deficit of cachectic muscle consists in increased fatigability, while the reported loss of tetanic force is not statistically significant following normalization for decreased muscle fiber size.ConclusionsWe conclude, on the basis of the definition of cachexia, that ectopically-implanted C26 carcinoma represents a well standardized experimental model for research on cancer cachexia. We wish to point out that scientists using the C26 model to study cancer and those using the same model to study cachexia may be unaware of each other's works because they use different keywords; we present strategies to eliminate this gap and discuss the benefits of such an exchange of knowledge.

A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia

“…In our experiments, we show that LIF originates from the C26 tumor and has a direct atrophic effect on skeletal muscle. The requirement of LIF also explains the loss of adipose tissue in C26 cancer cachexia (7,21).…”

“…To study cancer cachexia, animal tumor models have been used as systems in which the factors responsible for muscle and adipose loss can be isolated and tested more easily than in cancer patients. One of the most studied models is C26 colon adenocarcinoma in mice (5)(6)(7). Several different transcription factors, signaling pathways, and triggering ligands have been implicated in C26-induced skeletal muscle atrophy.…”

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

“…Since then, nearly 190 manuscripts have been written using the C26 adenocarcinoma cell line, which delineate the natural history of cachexia and its underlying mechanisms [8]. When placed in mice, the C26 adenocarcinoma cell line form tumors which secrete proinflammatory cytokines.…”

“…The C26 adenocarcinoma murine model of cancer cachexia was chosen as a model because it has been extensively characterized over the past 30 years to test chemotherapeutics in vivo [8]. C26 adenocarcinoma cells were placed in the right flank of BALB/c mice to induce cancer cachexia.…”

Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia

“…CD2F1 mice injected with C26 adenocarcinoma cells (5) are a recent established model to study cancer cachexia. In this model, tumor development is directly correlated with reduced cardiac function as measured by ejection fraction and fractional shortening (35).…”