Serum interleukin-6 in patients with metastatic bone disease: correlation with cystatin C

Tumminello, Francesca Maria; Badalamenti, Giuseppe; Incorvaia, Lorena; Fulfaro, Fabio; D’Amico, Calogero; Leto, Gaetano

doi:10.1007/s12032-008-9070-2

Cited by 34 publications

(35 citation statements)

References 34 publications

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“…A clinical correlation between this cytokine and cystatin C, an endogenous inhibitor of cysteine cathepsins such as cathepsin K, as well as between cystatin C and cathepsin K, has already been demonstrated in patients with prostate cancer-induced metastatic bone disease. 81,82 Both IL-6 and IL-8 are known to attract and activate osteoclasts and to play a role in prostate cancer. 49,53,83,84 Osteoclast formation by PC3-derived IL-6 and IL-8 was recently shown to be RANKL-independent.…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow-Derived Cathepsin K Cleaves SPARC in Bone Metastasis

Podgorski

Linebaugh

Koblinski

et al. 2009

The American Journal of Pathology

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Prostate and breast cancers commonly metastasize to skeletal sites and locally disrupt normal bone remodeling.Despite recent progress in cancer detection and treatment, it remains unclear which skeletal-specific factors are among the critical determinants in preferential localization of metastatic cells to the bone. Recent clinical and experimental data suggest that accelerated bone remodeling may be responsible for homing of tumor cells to the bone.1,2 This is evidenced by the increased metastasis in response to experimental treatment with calciotropic hormone or to androgen ablation 1,2 and reduced incidence of metastasis with antiresorptive therapies.3 Establishment of tumors in bone requires multidirectional interactions between tumor cells, bone cells, stromal cells, and inflammatory components, as well as extracellular matrix proteins. This complex interplay between tumor cells and the bone microenvironment facilitates increased bone turnover and promotes tumor cell survival.The key enzyme responsible for osteolysis of bone is the cysteine protease cathepsin K, which is the only known mammalian protease capable of degrading both the helical and non-helical regions of collagen I, the main component of the organic bone matrix. 4 Within the bone microenvironment, cathepsin K localizes predominantly to osteoclasts and its overexpression results in increased bone turnover.5 Accordingly, a deficiency in this potent collagenase results in a bone-sclerosing disorder called pycnodysostosis in man and osteopetrosis in mice. 6,7 The presence of cathepsin K has been demonstrated in many malignancies including prostate and breast cancers, both of which have a high propensity to metastasize to bone. 8 -10 A role for cathepsin K in advanced cancers has been attributed mainly to its ability to degrade native collagen I and facilitate the expansion of tumors in the bone. Our recent studies and data by other groups suggest that cathepsin K also cleaves and thereby modulates the biological activity of several important proteins in the bone microenvironment.11-15 Of particular importance is Supported by grants from the DOD PC030325. DOD PC074031. DOD

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Section: Discussionmentioning

confidence: 99%

Bone Marrow-Derived Cathepsin K Cleaves SPARC in Bone Metastasis

Podgorski

Linebaugh

Koblinski

et al. 2009

The American Journal of Pathology

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“…Serum IL-6 levels are significantly elevated in PCa patients and in addition a positive correlation between IL-6 levels and the number of bone metastases is also seen (Tumminello et al 2009). IL-6 is a growth and survival factor in human PCa cells with aggressive phenotypes and has been implicated in the progression of PCa to AIPC (Culig et al 2005, Wegiel et al 2008.…”

Section: Induction Of Mkp5 and Inhibition Of Stress-activated Kinase mentioning

confidence: 99%

Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment

Krishnan¹,

Feldman²

2010

Endocrine-Related Cancer

129

118

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Calcitriol, the hormonally active form of vitamin D, exerts multiple anti-proliferative and pro-differentiating actions including cell cycle arrest and induction of apoptosis in many malignant cells, and the hormone is currently being evaluated in clinical trials as an anti-cancer agent. Recent research reveals that calcitriol also exhibits multiple anti-inflammatory effects. First, calcitriol inhibits the synthesis and biological actions of pro-inflammatory prostaglandins (PGs) by three mechanisms: i) suppression of the expression of cyclooxygenase-2, the enzyme that synthesizes PGs; ii) up-regulation of the expression of 15-hydroxyprostaglandin dehydrogenase, the enzyme that inactivates PGs; and iii) down-regulation of the expression of PG receptors that are essential for PG signaling. The combination of calcitriol and nonsteroidal anti-inflammatory drugs results in a synergistic inhibition of the growth of prostate cancer (PCa) cells and offers a potential therapeutic strategy for PCa. Second, calcitriol increases the expression of mitogenactivated protein kinase phosphatase 5 in prostate cells resulting in the subsequent inhibition of p38 stress kinase signaling and the attenuation of the production of pro-inflammatory cytokines. Third, calcitriol also exerts anti-inflammatory activity in PCa through the inhibition of nuclear factor-kB signaling that results in potent anti-inflammatory and anti-angiogenic effects. Other important direct effects of calcitriol as well as the consequences of its anti-inflammatory effects include the inhibition of tumor angiogenesis, invasion, and metastasis. We hypothesize that these anti-inflammatory actions, in addition to the other known anti-cancer effects of calcitriol, play an important role in its potential use as a therapeutic agent for PCa. Calcitriol or its analogs may have utility as chemopreventive agents and should be evaluated in clinical trials in PCa patients with early or precancerous disease.

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“…High levels of IL-6 in serum are associated with more voluminous tumours, higher Gleason score and the presence of lymph node metastases (21,22). These levels are dramatically elevated in patients with PCa metastatic to bone (23). Plasma levels of IL-6 and its soluble receptor in patients with clinically localized PCa are independent predictors of biochemical progression after surgery.…”

Section: Introductionmentioning

confidence: 99%

Soluble E-cadherin and IL-6 serum levels in patients affected by prostate cancer before and after prostatectomy

Sica¹

2012

Oncol Rep

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Abstract. Prostate specific antigen (PSA) is still the best available tumour marker in prostate cancer (PCa), but presents some limits. Therefore, there is a need for novel markers in the detection and management of PCa. The 80-kDa soluble form of E-cadherin (sE-cad) and the cytokine IL-6 are being discussed as supplemental serum markers for PCa. In this study, sE-cad and IL-6 serum levels were determined in patients with pathological localized or locally advanced PCa without any previous treatment. These patients underwent radical retropubic prostatectomy (RRP) in accordance with the EAU Guidelines on Prostate Cancer. The molecules were determined via immunoenzymatic assays in samples collected before and after surgery. Statistical analysis was performed by Student's t-test and Pearson's correlation test. sE-cad levels were 6.0±2.7 and 4.6±2.3 µg/ml, before and after RRP, respectively. A highly statistically significant decrease in sE-cad concentrations after RRP was observed (P<0.0001), in 50/61 patients (82%). sE-cad levels before and after surgery were correlated (Pearson's correlation coefficient, r=0.6993, P<0.0001). sE-cad values detected after surgery were higher in patients with PSA levels >10 ng/ml (P<0.05). sE-cad levels before RRP were significantly higher in patients with G3 tumours compared to those with G2 tumours (P<0.02). Finally, sE-cad concentrations both before and after surgery were higher in tumours with Gleason score =7 compared to those with Gleason score <7 (P<0.002 and P<0.05, respectively). Preliminary data from 20 patients indicated a statistically significant increase in IL-6 levels after RRP (11.2 vs. 7.2 pg/ml, P<0.001). This is the first study on the reduction in sE-cad levels after RRP in PCa patients. Moreover, it shows that preoperative sE-cad concentrations are higher in patients with less differentiated PCa. Promising findings of this pilot study may lead to investigation of sE-cad in a larger study with follow-up.

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Serum interleukin-6 in patients with metastatic bone disease: correlation with cystatin C

Cited by 34 publications

References 34 publications

Bone Marrow-Derived Cathepsin K Cleaves SPARC in Bone Metastasis

Bone Marrow-Derived Cathepsin K Cleaves SPARC in Bone Metastasis

Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment

Soluble E-cadherin and IL-6 serum levels in patients affected by prostate cancer before and after prostatectomy

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