Metastasis and cachexia: alongside in clinics, but not so in animal models

Abstract

Cancer cachexia is a paraneoplastic syndrome characterized by lean mass wasting (with or without fat mass decrease), culminating in involuntary weight loss, which is the key clinical observation nowadays. There is a notable lack of studies involving animal models to mimic the clinical reality, which are mostly patients with cachexia and metastatic disease. This mismatch between the clinical reality and animal models could at least partly contribute to the poor translation observed in the field. In this paper, we retrieved and compared animal models used for cachexia research from 2017 and 10 years earlier (2007) and observed that very little has changed. Especially, clinically relevant models where cachexia is studied in an orthotopic or metastatic context were and still are very scarce. Finally, we described and supported the biological rationale behind why, despite technical challenges, these two phenomena—metastasis and cachexia—should be modelled in parallel, highlighting the overlapping pathways between them. To sum up, this review aims to contribute to rethinking and possibly switching the models currently used for cachexia research, to hopefully obtain better and more translational outcomes.

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

“…This native environment is crucial in determining the biological behaviour of both the tumour and subsequent systemic response that induces cachexia . Tumour metastasis to the liver and lungs occurs in this model, which has been shown to be an important factor in the cachectic syndrome and is not a common feature in many pre‐clinical cancer cachexia models . Furthermore, by transplanting tumours from PDAC patients into mice, cachexia is investigated through the lens of soluble factors derived from a patient tumour, which likely varies between individual cancer patients .…”

Systemic Actions of Breast Cancer Facilitate Functional Limitations

“…With disease progression, breast cancer causes dramatic systemic effects. Myopenia and cachexia under metastatic settings are observed in~25% of breast cancer patients, particularly in women with triple-negative breast cancer [1,2]. Functional limitations are observed even before cancer diagnosis and are the major reasons for increased no-cancer related deaths in these patients [3,4].…”

“…The limited progress is mainly due to the perception that breast cancer patients, compared to other cancer patients, rarely experience cachexia. However, considering one in eight women in the United States is diagnosed with breast cancer and 25% of breast cancer patients, particularly those with triple-negative breast cancer, experience cachexia [2,174], additional studies are needed. Furthermore, myopenic obesity, which not only provides a misguided outlook but also impacts chemotherapy tolerability [26,175], is common in breast cancer patients.…”

Journal of Cachexia, Sarcopenia and Muscle

“…3 Unfortunately, the prevalence of cachexia-induced mortality in cancer patients remains unchanged from the initial mortality estimations in 1932, 4,5 as current modeling systems are limited and therapeutic interventions ineffective. [5][6][7] While the terminology used to describe cancer cachexia has varied, cancer cachexia in the presence of comorbid anorexia is associated with higher morbidity and mortality, and is termed Cancer Anorexia Cachexia Syndrome (CACS). 8 Defining the pathology of, and therapeutic response to, cachexia has largely relied on animal model systems 6,7 ; however, no established model comprehensively recapitulates the multifactorial CACS limiting clinical advancements.…”

“…[5][6][7] While the terminology used to describe cancer cachexia has varied, cancer cachexia in the presence of comorbid anorexia is associated with higher morbidity and mortality, and is termed Cancer Anorexia Cachexia Syndrome (CACS). 8 Defining the pathology of, and therapeutic response to, cachexia has largely relied on animal model systems 6,7 ; however, no established model comprehensively recapitulates the multifactorial CACS limiting clinical advancements. Of note, many model systems do not metastasize significantly despite consistent clinical reports demonstrating a higher incidence of cachexia and its comorbidities in the advanced metastatic stage.…”