Expression of TNF‐α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas

Abstract

Tumor necrosis factor-a (TNF-a) is involved in epithelial-mesenchymal transition (EMT) and expression of CD44, a cancer stem cell marker, in several cancers. This study was performed to clarify the significance of TNF-a and CD44 in clear cell renal cell carcinomas (ccRCCs). Expression of TNF-a and CD44 was examined by immunohistochemistry in 120 ccRCCs. Involvement of TNF-a in EMT and induction of CD44 was analyzed by monitoring expression of EMT-related genes and CD44, and invasion in cultured ccRCC cell lines. TNF-a and CD44 were immunolocalized mainly to carcinoma cells of high-grade ccRCCs with positive correlations with primary tumor stage. A positive correlation was also obtained between TNF-a and CD44 expression, and co-upregulation of TNF-a and CD44 was associated with primary tumor stage, distant metastasis, and poor prognosis. TNF-a enhanced migration and invasion of ccRCC cells together with down-regulation of E-cadherin expression and up-regulation of matrix metalloproteinase 9 and CD44 expression. TNF-a also up-regulated the expression of TNF-a itself in ccRCC cells. Among the 25 ccRCC patients treated with sunitinib for metastatic disease, high CD44 expression was associated with poor treatment outcome. Importantly, residual carcinoma cells in the sunitinib-treated metastatic ccRCCs were strongly positive for CD44, and the CD44 expression was significantly higher in the tumors from the sunitinib-treated patients than in those from untreated ones. Our data show that TNF-a plays an important role in progression of ccRCCs by inducing EMT and CD44 expression, and suggest that CD44 induced by TNF-a may be involved in the resistance to the sunitinib treatment.Cancer-related inflammation accelerates tumor cell proliferation and angiogenesis.1 Tumor necrosis factor-a (TNF-a) is an important mediator for the inflammatory responses in cancers, and infiltrated macrophages are a major source of TNF-a.2 Although TNF-a was originally reported as a cytokine to induce apoptotic cell death and cachexia, 1 accumulated lines of evidence indicate that TNF-a has tumorpromoting effects. 2 Actually, TNF-a produced by tumor cells is known to induce tumor cell proliferation and progression by autocrine and paracrine manners in ovarian cancers, 3 and TNF-a enhances epithelial-mesenchymal transition (EMT) of clear cell renal cell carcinoma (ccRCC) cells in vitro.4 TNF-a

Original paper Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms

“…In a combined group of pulmonary and gastrointestinal neuroendocrine neoplasms originally described as carcinoids, the patients with lymph node or distant metastasis lacked CD44 in the tumours significantly more frequently [85]. Thus, the prognostic role of CD44 expression in NENs is different from the negative findings in many carcinomas, including pancreatic ductal adenocarcinoma, gastric adenocarcinoma, clear cell renal carcinoma or non-small cell lung carcinoma, among others [11,[86][87][88]. In our study, there also was no association between CD44 and such morphological parameters, such as high grade and stage, which are indicative of a poor prognosis.…”

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…Considering immunoexpression, Mikami et al [55] studied a subset of 25 Japanese mRCC patients on sunitinib. Herein, a high expression of the cancer stem cell marker CD44 was associated with a poor treatment outcome and responsible for developing sunitinib resistance.…”

“…Herein, a high expression of the cancer stem cell marker CD44 was associated with a poor treatment outcome and responsible for developing sunitinib resistance. Also, the combination of high expression of TNF-α and CD44 was associated with a decreased PFS [55]. Dornbusch et al [56] evaluated the immunoexpression of tumor protein markers in 42 patients with mRCC.…”

The Great Escape; the Hallmarks of Resistance to Antiangiogenic Therapy

“…Targeting CD44 may also benefit cancer therapy through an independent mechanism recently described in renal cell carcinoma (Mikami et al, 2015). Direct targeting of said molecules might provide a therapeutic option as would be the circumvention of hypoxia that contributes to induction of vasculogenic mimicry Xu et al, 2012).…”