Systemic Inflammation in Cachexia – Is Tumor Cytokine Expression Profile the Culprit?

Abstract

Cachexia affects about 80% of gastrointestinal cancer patients. This multifactorial syndrome resulting in involuntary and continuous weight loss is accompanied by systemic inflammation and immune cell infiltration in various tissues. Understanding the interactions among tumor, immune cells, and peripheral tissues could help attenuating systemic inflammation. Therefore, we investigated inflammation in the subcutaneous adipose tissue and in the tumor, in weight stable and cachectic cancer patients with same diagnosis, in order to establish correlations between tumor microenvironment and secretory pattern with adipose tissue and systemic inflammation. Infiltrating monocyte phenotypes of subcutaneous and tumor vascular-stromal fraction were identified by flow cytometry. Gene and protein expression of inflammatory and chemotactic factors was measured with qRT-PCR and Multiplex Magpix® system, respectively. Subcutaneous vascular-stromal fraction exhibited no differences in regard to macrophage subtypes, while in the tumor, the percentage of M2 macrophages was decreased in the cachectic patients, in comparison to weight-stable counterparts. CCL3, CCL4, and IL-1β expression was higher in the adipose tissue and tumor tissue in the cachectic group. In both tissues, chemotactic factors were positively correlated with IL-1β. Furthermore, positive correlations were found for the content of chemoattractants and cytokines in the tumor and adipose tissue. The results strongly suggest that the crosstalk between the tumor and peripheral tissues is more pronounced in cachectic patients, compared to weight-stable patients with the same tumor diagnosis.

Peritumoural adipose tissue pro‐inflammatory cytokines are associated with tumoural growth factors in cancer cachexia patients

“…In the present study, the major differences in cytokine levels between the groups were that the IL‐6 serum concentration and TNF‐α content in peritumoural adipose tissue were higher in the CC group patients than in the WSC group patients. In contrast, de Matos‐Neto et al . did not detect a difference in the TNF‐α protein content of subcutaneous adipose tissue and tumours between cachexia and stable weight patients.…”

“…Previously, our group reported that tumours from cachectic and stable weight cancer patients with the same diagnosis showed different secretory profiles of inflammatory factors and different proportions of macrophage phenotypes, with lower levels of M2 macrophages in the tumours of the cachectic patients. Based on these findings, we proposed an association between tumour‐originating factors and adipose tissue inflammatory changes, as a positive correlation was found between cytokines derived from the tumour and subcutaneous adipose tissue and inflammatory factors.…”

MyD88 signalling is critical in the development of pancreatic cancer cachexia

“…The liver tissue was analysed for gene expression of inflammatory mediators that are linked to cancer cachexia . Multiple genes, including Il1b , Il1r1 , Il6 , Il10 , Tnf , Ifng , Selp , Ccl2 , Crp , and Myd88 were upregulated in WT KPC mice relative to sham mice.…”

“…During cancer progression, tumour‐derived and host‐derived mediators promote excessive inflammation that worsens underling disease and accelerates catabolism, ultimately leading to cachexia . This circumstance is common in many cancers but is particularly ubiquitous and severe in pancreatic cancer .…”

“…In this way, the response to PDAC is similar to that observed after exposure to bacterial endotoxin, viral RNA, or cytokines, each of which induces robust inflammation that results in anorexia, body weight loss, fatigue, and muscle wasting . Over the past decade, studies in both humans and rodents implicate a number of pro‐inflammatory cytokines as key mediators of cachexia in PDAC, including tumour necrosis factor alpha, interleukin‐1 beta, interleukin‐6 (IL‐6), and interferon gamma . This in turn led to efforts at developing anti‐cytokine agents (e.g.…”