Elevated Serum Interleukin-6 Levels in Patients with Pancreatic Cancer

Okada, Shuichi; Okusaka, Takuji; Ishii, Hiroshi; Kyogoku, Akiko; Yoshimori, Masayoshi; Kajimura, Naoko; Yamaguchi, Ken; Kakizoe, Tadao

doi:10.1093/jjco/28.1.12

Cited by 117 publications

(86 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Circulating concentrations of proinflammatory cytokines are difficult to measure and interpret in human health and disease. In cancer cachexia, IL-1 is infrequently detected, whereas IL-6 is more frequently found to be elevated (18,19). Thus in the present study only serum IL-6 concentrations were measured.…”

Section: Discussionmentioning

confidence: 90%

Pro-inflammatory cytokine release by peripheral blood mononuclear cells from patients with advanced pancreatic cancer: Relationship to acute phase response and survival

Moses

Maingay²,

Sangster³

et al. 2009

Oncol Rep

View full text Add to dashboard Cite

Abstract. The acute phase protein response (APPR) and peripheral blood mononuclear cell-derived inflammatory cytokine production was assessed in patients with advanced pancreatic cancer and age-matched healthy volunteers. We examined the relationship between the APPR, cytokine production and survival in these patients. Forty-two patients with pancreatic cancer cachexia and twelve age-matched healthy controls were recruited. The nutritional status, Karnofsky performance score, C reactive protein (CRP), serum interleukin-6, and in vitro monocyte interleukin-1 and interleukin-6 production were measured. The dates of death of the pancreatic cancer patients were subsequently obtained and appropriate patient variables at baseline were entered into a Cox's proportional hazards model. The cancer patients had significantly lower: body mass index, Karnofsky performance score, serum albumin and elevated CRP and stimulated interleukin-6 production. Both univariate and multivariate analysis demonstrated a strong association between tumour stage, CRP, stimulated interleukin-6 production and survival. Monocytes in cachectic pancreatic cancer patients are primed to produce high levels of interleukin-6 when stimulated. Overproduction of interleukin-6 has a negative impact on survival. Decreased survival is associated with an elevated APPR. While the elevated APPR is probably related to locally produced interleukin-6 in the liver, it seems possible that locally and systemically produced interleukin-6 influences survival.

show abstract

Section: Discussionmentioning

confidence: 90%

Pro-inflammatory cytokine release by peripheral blood mononuclear cells from patients with advanced pancreatic cancer: Relationship to acute phase response and survival

Moses

Maingay²,

Sangster³

et al. 2009

Oncol Rep

View full text Add to dashboard Cite

show abstract

“…For example, high IL-6 levels have been associated with increased inflammation (20) and weight loss in patients with non-small-cell lung, pancreatic, and prostate cancers (19,46,51). However, other studies have suggested that cancer cachexia is not fully attributable to IL-6 levels (53).…”

Section: Discussionmentioning

confidence: 99%

New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line

Terawaki

Sawada²,

Kashiwase

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Although stomach cancer patients have the highest incidence of cachexia, few experimental models for the study of stomach CC have been established. Herein, we developed stomach CC animal models using nude rats subcutaneously implanted with two novel cell lines, i.e., MKN45c185, established from the human stomach cancer cell line MKN-45, and 85As2, derived from peritoneal dissemination of orthotopically implanted MKN45c185 cells in mice. Both CC models showed marked weight loss, anorexia, reduced musculature and muscle strength, increased inflammatory markers, and low plasma albumin levels; however, CC developed earlier and was more severe in rats implanted with 85As2 than in those implanted with MKN45cl85. Moreover, human leukemia inhibitory factor (LIF), a known cachectic factor, and hypothalamic orexigenic peptide mRNA levels increased in the models, whereas hypothalamic anorexigenic peptide mRNA levels decreased. Surgical removal of the tumor not only abolished cachexia symptoms but also reduced plasma LIF levels to below detectable limits. Importantly, oral administration of rikkunshito, a traditional Japanese medicine, substantially ameliorated CC-related anorexia and body composition changes. In summary, our novel peritoneal dissemination-derived 85As2 rat model developed severe cachexia, possibly caused by LIF from cancer cells, that was ameliorated by rikkunshito. This model should provide a useful tool for further study into the mechanisms and treatment of stomach CC. cachexia; leukemia inhibitory factor; rikkunshito; stomach cancer model; anorexia CANCER CACHEXIA, A MULTIFACTORIAL SYNDROME characterized by anorexia and the loss of body weight, adipose tissue, and skeletal muscle, is observed in 80% of advanced cancer patients and accounts for at least 20% of cancer-related deaths (20,35,42). This syndrome causes not only poor quality of life (QOL) but also poor responses to chemotherapy, highlighting the need for improved cancer cachexia treatments. Weight loss, the most prominent clinical feature of cachexia, is observed in 30 -80% of cancer patients, depending on tumor type. For example, weight loss occurs at a very high frequency (83%) in stomach and pancreatic cancer patients but is less prominent in patients with breast cancer, acute nonlymphocytic leukemia, and sarcomas (35). Although cachexia strongly impacts the success of therapeutic treatments, the mechanisms underlying this syndrome are not fully understood. Stomach cancer patients in particular have the highest incidence of cachexia; however, few experimental models for the study of stomach cancer cachexia have been established (4,14,66).A useful cachexia model must meet three of the following five diagnostic criteria in addition to weight loss: anorexia, decreased muscle strength, fatigue, low fat-free mass (FFM) index, and abnormal biochemistry (anemia, in...

show abstract

“…Dysregulated activation of STAT signaling is involved in the development of several human cancers (21). IL-6 is a cytokine with a unique capacity to activate STAT3 in both immune and cancer cells (22) and is elevated in the serum of patients with pancreatic cancer (23). IL-6 transsignaling promotes STAT3 phosphorylation and the subsequent development and progression of PanIN lesions in the KC genetically engineered model (13,24).…”

Section: Discussionmentioning

confidence: 99%

The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia

Kang

Loux

Tang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

137

133

View full text Add to dashboard Cite

Pancreatic cancer is an almost uniformly lethal disease, characterized by late diagnosis, early metastasis, resistance to chemotherapy, and early mutation of the Kras oncogene. Here we show that the receptor for advanced glycation endproducts (RAGE) is required for the activation of interleukin 6 (IL-6)-mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis. RAGE expression correlates with elevated levels of autophagy in pancreatic cancer in vivo and in vitro, and this heightened state of autophagy is required for IL-6-induced STAT3 activation. To further explore the intersection of RAGE, autophagy, and pancreatic carcinogenesis, we created a transgenic murine model, backcrossing RAGE-null mice to a spontaneous mouse model of pancreatic cancer, Pdx1-Cre:Kras G12D/+ (KC). Targeted ablation of Rage in KC mice delayed neoplasia development, decreased levels of autophagy, and inhibited mitochondrial STAT3 activity and subsequent ATP production. Our results suggest a critical role for RAGE expression in the earliest stages of pancreatic carcinogenesis, potentially acting as the "autophagic switch," regulating mitochondrial STAT3 signaling.oncogenesis | bioenergetics | inflammation | metabolism | high-mobility group box 1 P ancreatic cancer ranks as the fourth leading cause of cancer death, accounting for 6-7% of all cancer-related deaths in the United States, in 2011 (1). Most pancreatic ductal adenocarcinomas (PDA) are thought to arise from well-defined precursor lesions, termed pancreatic ductal intraepithelial neoplasia (PanIN) (2). Many human PanIN lesions do not progress to invasive carcinomas, so defining the events that drive carcinogenesis in the emergent tumor microenvironment is of critical importance. Studies into human pancreatic carcinogenesis have been greatly facilitated by the development of a genetically engineered mouse model that expresses oncogenic Kras under a pancreatic promoter Pdx1-Cre:Kras G12D/+ (KC) (3). A more detailed understanding of how these pathways accelerate pancreatic carcinogenesis may allow improved therapeutic strategies.The receptor for advanced glycation endproducts (RAGE) is a member of the Ig superfamily. RAGE and its ligands, including high-mobility group box 1 (HMGB1) and S100, are linked to the development and progression of several cancers by facilitating the maintenance of a chronic inflammatory state (4) and/or by promotion of metastases (5). We previously observed that RAGE sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival during chemotherapy and oxidative stress in vivo and in vitro (6, 7). Autophagy is an essential catabolic process by which cells break down old or damaged organelles and proteins (8). Autophagy promotes cell survival and supports metabolism during cell stress (9). Conversely, apoptosis promotes tumor growth early in the development of cancer (10) during periods of inhibition of autophagy with a subsequent switch to suppressed apoptosis, acquired later...

show abstract

Elevated Serum Interleukin-6 Levels in Patients with Pancreatic Cancer

Cited by 117 publications

References 16 publications

Pro-inflammatory cytokine release by peripheral blood mononuclear cells from patients with advanced pancreatic cancer: Relationship to acute phase response and survival

Pro-inflammatory cytokine release by peripheral blood mononuclear cells from patients with advanced pancreatic cancer: Relationship to acute phase response and survival

New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line

The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia

Contact Info

Product

Resources

About