Elena Maria Tosca (1), Antonio Montanaro (1), Maurizio Rocchetti (2), Paolo Magni (1)
(1) Department of Electrical, Computer and Biomedical Engineering, University of Pavia, via Ferrata 5, Pavia, I-27100, Italy, (2) Consultant, Milano, Italy
Introduction: Cancer cachexia is defined as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (sarcopenia) with or without loss of fat mass that cannot be fully reversed by conventional nutritional support (1). Body weight loss (BWL) is caused by a negative energy balance due to reduced food intake (anorexia) and altered metabolism. Cancer cachexia affects 50-80% of cancer patients and accounts for about 20% of cancer deaths. The lack of successful treatments likely relies on the difficulties in generating appropriate clinical trials to evaluate potential new therapies. In this context, an adequate use of appropriate animal models of cancer anorexia and cachexia is needed and making the most of the data collected from these experiments is fundamental (2,3).
Objectives: Recently, a Dynamic Energy Budget (DEB)-based tumor-in-host model was developed for a more efficient analysis of typical anticancer experiments in rodents (4,5). Aim of the present work is to further investigate the capabilities of the DEB-based framework in describing BWL, anorexia and body composition changes in tumor-bearing (TB) animals during preclinical studies of cancer cachexia.
Methods: Experimental: Preclinical studies performed on mice and rats and involving different tumor models (Walker-256 carcinoma, Yoshida sarcoma, C26 carcinoma, A2058 human melanoma, S2-013 human pancreatic cancer) were taken from literature (6-9). Experiments included tumor-free (TF) and TB animals with ad libitum feeding and pair fed (PF) healthy animals miming tumor-induced anorexia. Available data related to host BW, tumor weights (TW), daily or cumulative food intake, weights/diameter of gastrocnemius muscle and of epididymal adipose tissue (two measurements representative of the animal body composition). Modeling: Following the DEB-theory, the host body was split in two components: the structural biomass (Wv) and the energy reserve (We) which dynamics followed by energy balances. Tumor was conceived as an additional component able to subtract a fraction of the host energy. As tumor exploits host resources, in certain conditions, the host can even degrade its structural biomass to survive and, at the same time, to satisfy the tumor energy demand (sarcopenia). This condition can be further worsened by the negative impact of tumor progression on host food-intake (anorexia).
Results: Host-related, tumor-related and cachexia-related model parameters were successfully identified on host BW and TW measurements of TF and TB groups. To specifically assess the performances of the tumor-anorexia model, the predicted energy-intake was compared to the experimental data of daily or cumulative food-intake. The different tumor cell lines studied in the considered experiments showed a quite different effect on the food-consumption, inducing an intake reduction that ranged from <5% up to 50%. In all the situations, the model excellently predicted the food-intake reduction due to tumor progression, accounting for the different grade of tumor-induced anorexia. For the preclinical studies that included pair-fed healthy animals, BW dynamics of this group were used to further test the tumor-anorexia model. BWLs in PF group were well predicted by the model that was then able to discern body weight alterations due to reduced feeding from the one due to tumor energy consumption. Model capabilities in describing body composition changes induced by tumor progression were evaluated too. The energy reserve (We) and structural biomass (Wv) predicted by the model were compared to the dynamics of adipose tissue (epidydimal mass) and skeletal muscle (gastrocnemius weight/diameter) data. A qualitative agreement was found. In particular, in accordance with the experimental data, model showed that BWLs in TB animals were caused by decreases of both We (adipose tissue) and Wv (skeletal muscle). Differently, in TF animals, fasting affected We (adipose tissue) more than Wv (muscle).
Conclusions: Obtained results confirmed the ability of the tumor-in-host DEB-based model (4,5) in describing and predicting the key endpoints of cancer-cachexia in animal studies. In particular, the model was able to account for tumor burden, BWL, food-intake reduction and body composition changes induced by tumor progression. For these reasons, the model seems to be a useful tool to further investigate the complexities of cancer cachexia.
References:
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[5] Tosca, E. M., et al. A Population Dynamic Energy Budget-Based Tumor Growth Inhibition Model for Etoposide Effects on Wistar Rats. Pharmaceutical research 36.3 (2019): 38.
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[7] Guaitani, A., Torre, P. D., Morasca, L., Pintus, C., & Bartošek, I. (1983). Two lines of Walker carcinoma 256: their peculiarities and different interactions with the host. Tumori Journal, 69(1), 1-9.
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[9] Jourdain, M., Melly, S., Summermatter, S., & Hatakeyama, S. (2018). Mouse models of cancer-induced cachexia: Hind limb muscle mass and evoked force as readouts. Biochemical and biophysical research communications, 503(4), 2415-2420.
Reference: PAGE 29 (2021) Abstr 9879 [www.page-meeting.org/?abstract=9879]
Poster: Drug/Disease Modelling - Oncology