Exploring heterogeneity: a dive into preclinical models of cancer cachexia

Abstract

Cancer cachexia (CC) is a multifactorial and complex syndrome experienced by up to 80% of patients with cancer and implicated in ∼40% of cancer-related deaths. Given its significant impact on patients' quality of life and prognosis, there has been a growing emphasis on elucidating the underlying mechanisms of CC using preclinical models. However, the mechanisms of cachexia appear to differ across several variables including tumor type and model and biologic variables such as sex. These differences may be exacerbated by variance in experimental approaches and data reporting. This review examines literature spanning from 2011 to March 2024, focusing on common preclinical models of CC, including Lewis Lung Carcinoma, pancreatic KPC, and colorectal colon-26 and Apc^min/+ models. Our analysis reveals considerable heterogeneity in phenotypic outcomes, and investigated mechanisms within each model, with particular attention to sex differences that may be exacerbated through methodological differences. Although searching for unified mechanisms is critical, we posit that effective treatment approaches are likely to leverage the heterogeneity presented by the tumor and pertinent biological variables to direct specific interventions. In exploring this heterogeneity, it becomes critical to consider methodological and data reporting approaches to best inform further research.

Keywords: ApcMin/+; KPC; Lewis lung carcinoma (LLC); biological sex; colon-26 (C26).

Graphical abstract

Figure 1.

Summary of known factors impacting cancer cachexia heterogeneity. Cancer cachexia’s development is affected by many features such as aging, comorbidities, anticancer and cancer management treatments, cancer type and severity, as well as biological sex. In turn, characteristics of cancer cachexia manifest in a biological sex-specific and muscle-specific manner even in similar conditions. Moreover, preclinical research needs to account for the aforementioned features, as well as mice strain, age of induction, and cancer induction methods, as well as establishing cancer-specific methodologies and data reporting practices that will allow data to be shared and fairly compared between different research groups. Created with BioRender.com.

Figure 2.

Preclinical phenotypic characteristics in Lewis lung carcinoma (LLC), pancreatic orthotopic KPC, colon-C26, Apc^Min/+, and transgenic KPC models. Model and range of cells injected (far left; A), tumor burden (B), mouse strain/background and range of age at induction (C), tumor development length in weeks, and body weight (BW) loss in percent in males and females (D), and range of percent muscle loss of soleus, gastrocnemius (GC), and tibialis anterior (TA) (E) per sex. IP, intraperitoneal; NS/NR, nonsignificant/nonreported; OT, orthotopic; SC, subcutaneous; W.O., week-old. Text colored in blue represents male, and text in pink is female-derived data. Created with BioRender.com.