The Contribution of Tumor Derived Exosomes to Cancer Cachexia

Abstract

Cancer cachexia is defined as unintentional weight loss secondary to neoplasia and is associated with poor prognosis and outcomes. Cancer cachexia associated weight loss affects both lean tissue (i.e., skeletal muscle) and adipose tissue. Exosomes are extracellular vesicles that originate from multivesicular bodies that contain intentionally loaded biomolecular cargo. Exosome cargo includes proteins, lipids, mitochondrial components, and nucleic acids. The cargo carried in exosomes is thought to alter cell signaling when it enters into recipient cells. Virtually every cell type secretes exosomes and exosomes are known to be present in nearly every biofluid. Exosomes alter muscle and adipose tissue metabolism and biological processes, including macrophage polarization and apoptosis which contribute to the development of the cachexia phenotype. This has led to an interest in the role of tumor cell derived exosomes and their potential role as biomarkers of cancer cell development as well as their contribution to cachexia and disease progression. In this review, we highlight published findings that have studied the effects of tumor derived exosomes (and extracellular vesicles) and their cargo on the progression of cancer cachexia. We will focus on the direct effects of tumor derived exosomes and their cellular cross talk on skeletal muscle and adipose tissue, the primary sites of weight loss due to cancer cachexia.

Keywords: adipocytes; adipose; cachexia; exosomes; extracellular vesicles; inflammation; metabolism; muscle.

Figure 1

Exosome release in noncancerous cells is generally a pro-survival mechanism that is meant to relay signals of cellular stress throughout the body. Exosome release from tumor cells serves the same purpose, however tumor cells are exposed to a multitude of cellular stresses that stimulate exosome release. These exosomes interact with the tumor microenvironment and enter circulation where they exert systemic effects. (A) Tumor derived exosome release is stimulated by hypoxia to promote cell survival by altering the ECM components of the tumor microenvironment, stimulating angiogenesis, altering tumor and host cell metabolism, and altering local macrophage polarization. (B) Circulating inflammatory mediators also stimulate exosome release from tumor cells. These exosomes directly impact the MPS/MPB balance, increase E3 ubiquitin ligase expression, increase lipolysis and cause adipose tissue browning. Collectively, these effects illustrate a clear role of tumor derived exosomes in supporting cancer cell survival and contributing to the development of CC. Exosomes represent a novel potentially important therapeutic target for countering CC.

Figure 2

Exosome regulation of muscle and adipose wasting in cancer cachexia. Tumor cells secrete a range of exosomes which differ based on the tumor type. Nevertheless, common features of exosomes include a tumor regulated inflammatory environment which stimulates cytokine and E3 ligase activation in skeletal muscle along with an upregulation of signaling for apoptosis, reduced myocyte protein synthesis, and increased muscle protein degradation. Furthermore, tumor derived exosomes stimulate a dysregulated metabolic phenotype in skeletal muscle. Similarly, tumor derived exosomes decrease adipogenesis, increase browning of adipose cells and increase lipolysis, which contributes to overall loss of adipose stores. The resultant loss of skeletal muscle and adipose tissue is defined as cancer cachexia.