Hallmarks of Cancer Cachexia: Sexual Dimorphism in Related Pathways

Abstract

Cancer-associated cachexia (CAC), also known as wasting syndrome, is a systemic condition that affects multiple tissues and organs via a variety of metabolic pathways. Systemic inflammation, progressive weight loss, depletion of adipose tissue, and skeletal muscle impairment are some of the hallmark features of cachexia. Despite various studies on the clinical features of CAC, the complexity of the syndrome continues to pose significant challenges in clinical practice, leading to late diagnoses and the absence of a standardised treatment. Men and women respond differently to CAC, which may be prompted by the pre-existing physiologic sex differences. This review presents the sexual dimorphism associated with the hallmark pathways involved in CAC. A comprehensive understanding of sexual dimorphism in these pathways could drive research on cachexia to prioritise the inclusion of more females in related studies in order to achieve personalised sex-based therapeutic approaches and, consequently, enhance treatment efficacy and better patient outcomes.

Keywords: cachexia; cancer; hallmarks; sex hormones; sexual dimorphism.

Figure 1

The hallmarks of cancer-associated cachexia (CAC). This illustration encompasses six hallmark features involved in the development of CAC.

Figure 2

Overall and sex-specific prevalence of cancer-associated cachexia (CAC) in eight studies arranged in chronological order of publication. The tumour type assessed in each study is presented under each group of bars. Two studies included patients with different tumour types. Study 1 included patients with breast, GI tract, lung, and head and neck cancer, while study 2 included patients with colorectal, hepato-pancreato-biliary, skin/soft tissue, breast, and other cancers [20,21,22,23,24,25,26,27].

Figure 3

Interaction of sex hormones with cytokines influences the risk of developing cancer-associated cachexia (CAC) due to systemic inflammation. IFNγ: interferon gamma; IL1β: interleukin-1 beta; IL6: interleukin-6; IL10: interleukin-10; TNFα: tumour necrosis factor alpha. Interaction of sex hormones with cytokines influences the risk of developing cancer-associated cachexia (CAC) due to systemic inflammation. IFNγ: interferon gamma; IL1β: interleukin-1 beta; IL6: interleukin-6; IL10: interleukin-10; TNFα: tumour necrosis factor alpha. The balance of inflammation control is tilted towards the stronger part.

Figure 4

The effects of different molecules and hormones on the alterations of adipose tissue (AT). The figure shows a simplified promoting (shown in green plus) and inhibiting (shown in red cross) effect on each of the pathways involved in adipose tissue alterations, whether in cachexia or physiological conditions. The effects of each of these molecules are complex and multifaceted and differ in various contexts. Oestrogen specifically has dual effects on lipolysis depending on the type of AT and in each sex. ADRB3: beta 3 adrenergic receptor; FA: fatty acid; IL-6: interleukin-6; TNFα: tumour necrosis factor alpha.

Figure 5

Summary of sex differences observed in the muscles of cachectic cancer patients. The upper circles represent sex differences in muscle at the molecular level under normal physiological conditions and in cancer cachexia, while the lower squares represent the different outcomes between men and women in cancer cachexia. UPS: ubiquitin-proteasome system; O: oestrogen; P: progesterone; T: testosterone.