Selective up-regulation of tumor necrosis factor receptor I in tumor-bearing rats with cancer-related cachexia

Catalano, M.; Fortunati, Nicoletta; Arena, Katia; Costelli, Paola; Aragno, Manuela; Danni, Oliviero; Boccuzzi, Giuseppe

doi:10.3892/ijo.23.2.429

Cited by 24 publications

(26 citation statements)

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“…cytolytic cells. Alternative mechanisms that would need to be considered under this scenario would include differential susceptibility of cytotoxic T cells to apoptosis [58][59][60][61] between MSI-H and MSS tumors, and differential localized cytokine production that would enhance/inhibit tumor growth [62][63][64][65][66][67][68]. HNPCC tumors are Lymphocyte recruitment in MSI-H CRC 235 predominantly proximal in nature [69].…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer

et al. 2009

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The ability of the host to mount an appropriate immune response to aberrant cells is one factor that determines prognosis in cancer patients. Naturally occurring regulatory T cells (T regs; CD4+ CD25+ cells) are key regulators of peripheral tolerance. It has been suggested that high levels of T regs are detrimental to the patient in some forms of cancer, but the role of these antigen-specific cells in individuals with colorectal cancers with high levels of microsatellite instability is unknown. Herein, we examined the ability of individuals with MSI-H or microsatellite stable colon cancer to recruit lymphocytes to the tumor site. Immunohistochemical staining was performed on archived paraffin-embedded specimens from a total of 38 individuals with MSI-H (n = 25) or MSS (n = 13) colon cancers to determine the proportion of CD3+, CD8+ and CD25+ cells infiltrating the tumor site. Patients with MSI-H colon cancers had increased percentages of CD8+ TILs (cytotoxic T cells) as compared to individuals with MSS colon cancer (47.3 vs. 24.04% of the infiltrate CD8+, respectively). No differences in the levels of CD25+ T cells were observed between individuals with MSI-H colon cancers and MSS colon cancers (0.53 vs. 0.54% CD25+, respectively). Together, these data suggest that the survival advantage enjoyed by patients with MSI-H colorectal cancer may, in part, be attributed to the increased cytolytic response, but not to an antigen-specific immunosuppressive response in MSS patients.

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Section: Discussionmentioning

confidence: 99%

Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer

et al. 2009

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“…TRAPS presents clinically with self-limited inflammatory episodes (27). Therefore, in TRAPS patients, a proinflammatory event triggered by an environmental factor (such as infection [28,29], cancer [30,31], and drug toxicity [32]) that can up-regulate TNFRI expression will have an overall proinflammatory and antiapoptotic effect, because in the case of the T50K variant, which is capable of sustaining inappropriate NF-B activation, this will result in persistent production of proinflammatory mediators including TNF itself. A similar proinflammatory outcome has been shown in a mouse model of TRAPS (33).…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor–associated periodic syndrome interacts with wild‐type tumor necrosis factor receptor I and induces ligand‐independent NF‐κB activation

Yousaf¹,

Gould²,

Aganna³

et al. 2005

Arthritis & Rheumatism

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Objective. To investigate the molecular consequences of expressing mutated forms of tumor necrosis factor receptor I (TNFRI) as found in patients with TNFR-associated periodic syndrome (TRAPS).Methods. We cloned and expressed full-length wild-type (WT) and T50K and P46L variants of TNFRI using a new tightly regulated doxycycline-dependent expression system. This system enabled the study of molecular interactions between these receptors at both physiologic and pathophysiologic levels of expression.Results. We used chemical crosslinking on the cell surface to show that WT and mutant forms of TNFRI, derived from TRAPS patients, interact in the absence of TNF ligand. Doxycycline-controlled up-regulation of one TNFRI allele, either WT or mutant, caused downregulation of the other allele, indicating dynamic control of cell surface assembly. We also demonstrated that increased expression of mutant TNFRI (T50K) was associated with a parallel increase in NF-B p65 (RelA) subunit activation, which did not occur with increased expression of WT TNFRI.Conclusion. The T50K TRAPS-related variant is capable of sustaining inappropriate NF-B activation, resulting in persistent autoinflammation in target organs such as skin, synovial membrane, and the central nervous system. We conclude that some of the inflammatory processes seen in TRAPS do not involve direct interaction of TNF with its receptors, but that other proinflammatory mechanisms capable of up-regulating TNFRI expression may cause cellular activation through the NF-B signaling pathway.Tumor necrosis factor receptor-associated periodic syndrome (TRAPS; MIM no. 142680) is a dominantly inherited chronic inflammatory disorder caused by mutations in the extracellular domains of tumor necrosis factor receptor I (TNFRI), the gene for which is TNFRSF1A (1), and characterized by recurrent fevers and abdominal pain. The most common mutations involve cysteine residues, but several variants involving other residues have also been reported (1,2). More than 30 different pathogenic TNFRSF1A mutations have now been identified (see http://fmf.igh.cnrs.fr/infevers/ and ref.2), mostly located in either the first or second cysteine-rich N-terminal extracellular domain (CRD1 or CRD2) of TNFRSF1A (2,3). Impaired cleavage of the TNFRI (p55) ectodomain upon cellular activation has been demonstrated as a pathogenic mechanism in some but not all TNFRI variants (3-6) and did not relate to the severity of the phenotype (7,8).Biologic activities of TNF are mediated through 2 TNFRs, TNFRI and TNFRII (TNFR superfamily 1B

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“…IL-1 and IL-6 are upregulated in animal models of cancer-associated cachexia 102 , and IL-6 levels correlate with weight loss in certain human cancers [103][104][105][106] . Moreover, cachexia can be ameliorated in mice treated with IL-6-targeted antibodies 107 .…”

Section: Muscle Atrophy During Systemic Diseasementioning

confidence: 99%

Muscle wasting in disease: molecular mechanisms and promising therapies

Cohen

Nathan

Goldberg

2014

Nat Rev Drug Discov

900

850

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Atrophy occurs in specific muscles with inactivity (for example, during plaster cast immobilization) or denervation (for example, in patients with spinal cord injuries). Muscle wasting occurs systemically in older people (a condition known as sarcopenia); as a physiological response to fasting or malnutrition; and in many diseases, including chronic obstructive pulmonary disorder, cancer-associated cachexia, diabetes, renal failure, cardiac failure, Cushing syndrome, sepsis, burns and trauma. The rapid loss of muscle mass and strength primarily results from excessive protein breakdown, which is often accompanied by reduced protein synthesis. This loss of muscle function can lead to reduced quality of life, increased morbidity and mortality. Exercise is the only accepted approach to prevent or slow atrophy. However, several promising therapeutic agents are in development, and major advances in our understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting. Here, we discuss these new insights and the rationally designed therapies that are emerging to combat muscle wasting.

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Selective up-regulation of tumor necrosis factor receptor I in tumor-bearing rats with cancer-related cachexia

Cited by 24 publications

References 0 publications

Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer

Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer

Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor–associated periodic syndrome interacts with wild‐type tumor necrosis factor receptor I and induces ligand‐independent NF‐κB activation

Muscle wasting in disease: molecular mechanisms and promising therapies

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