Tumour inoculation site-dependent induction of cachexia in mice bearing colon 26 carcinoma

Abstract

Summary Murine colon 26 carcinoma growing at either subcutaneous (s.c.) or intramuscular (i.m.) inoculation sites causes cachexia in mice. Such animals show extensive loss of body weight, wasting of the muscle and adipose tissues, hypoglycaemia, and hypercalcaemia, even when the tumour weight comprises only about 1.9% of carcass weight. In contrast, the same tumour when inoculated into the liver does not cause any sign of tumour-related cachexia even when the tumour becomes much larger (6.6% of carcass weight). Interleukin 6 (IL-6), a mediator associated with cachexia in this tumour model, is detected at high levels both in the tumour tissues and in the circulating blood of mice bearing colon 26 tumour at the s.c. inoculation site. In contrast, only minute levels of IL-6 are detected in the tumour grown in the liver. The colon 26 tumour grown in the liver does not lose its ability to cause cachexia, because the tumour when re-inoculated s.c. is able to cause extensive weight loss and produce IL-6 as did the original colon 26 cell line. Histological studies revealed differences in the composition of tumour tissues: the tumours grown in the subcutis consist of many polygonal tumour cells, extended-intercellular space, and high vascular density, whereas those grown in the liver consist of spindle-shaped tumour cells. Thus, the environment where tumour cells grow would be a critical factor in determining the cachectic phenotype of cancer cells, including their ability to produce IL-6.

Dietary supplementation with a specific combination of high protein, leucine, and fish oil improves muscle function and daily activity in tumour-bearing cachectic mice

“…These data confirm earlier findings that for cachexia, validated C26 adenocarcinoma mouse model can be used as a cachectic non-anorectic model (Tanaka et al, 1990;Diffee et al, 2002;Gorselink et al, 2006) The observation, however, that in experiment A, food intake of Con is significantly higher than that of TB mice on day 20 specifically indicates that if tumour growth would continue for a few days more, the tumour-bearing animals would likely become anorectic. The differences in cachectic parameters between control and tumour-bearing mice 20 days after tumour inoculation, were comparable in magnitude to those described in other studies also using the C26 adenocarcinoma mouse model (Lazarus et al, 1996;Matsumoto et al, 1999;Samuels et al, 2000;Fujimoto-Ouchi et al, 2006;Gorselink et al, 2006).…”

The importance of tissue environment surrounding the tumor on the development of cancer cachexia

“…Use of the clone 5 tumor, which was established from a single cell in colon 26 adenocarcinoma, obviates the effect of selection of a tumor cell clone by the host's immune system, thereby facilitating experimental investigation of host factors in the present study. Indeed, inoculation of the clone 5 tumor does not result in inoculation site-dependent differences in the composition of cell clones that can otherwise be seen in other animal models where tumors were composed of many cell clones (13)(14)(15).…”

“…The importance of tissue environment surrounding the tumor on the development of cancer cachexia composition of tumor cells, and the selection of cancer cells in response to the host environment results in different clinical manifestations (13). Even when tumor cells are inoculated in nude mice with an immunological deficit, the metastatic capacity of the established tumor varies according to the site of the tumor (14,15).…”

Targeting Protein Synthesis in a Myc/mTOR-Driven Model of Anorexia-Cachexia Syndrome Delays Its Onset and Prolongs Survival

“…The underlying mechanisms responsible for ACS remains obscure, but are thought to be multifactorial, resulting from an imbalance of pro-and anti-inflammatory cytokines and orexigenic and anorexigenic factors (1). Altered expression of several cytokines and growth factors (e.g., TNF-a, IL-1, IL-6, IGF-1, and IFN-g) have been implicated in cancer cachexia (3)(4)(5)(6)(7)(8).…”

“…Ribosome recruitment is mediated by eukaryotic initiation factor (eIF)4F, a complex consisting of eIF4E, the cap (m 7 GpppN; where N is any nucleotide) binding protein; eIF4A, an RNA helicase; and eIF4G, a large scaffolding protein (10). mTOR regulates translation initiation rates by controlling the availability of eIF4E and eIF4A for assembly into the eIF4F complex (10).…”