TNF-α key player in RCC progression

By Laura Cowen, medwireNews Reporter

Tumour necrosis factor (TNF)- α appears to play a key role in the promotion of invasion and metastasis in clear cell renal cell carcinomas (ccRCCs), Japanese study findings indicate.

Shuji Mikami and colleagues, from Keio University in Tokyo, report that overexpression of the inflammatory cytokine predominantly occurs in high-grade ccRCC, and is associated with primary tumour stage and distant metastasis, along with decreased progression-free and overall survival.

The team studied tumours from 120 patients who underwent total or partial nephrectomy between 1991 and 2003.

The majority (80%) of the tumours showed positive TNF-α staining on immunohistochemistry, with diffuse patterns observed for high-grade (grades 3 and 4) tumours compared with mainly negative findings in low-grade (grades 1 and 2) tumours.

Similar results were observed for staining of CD44, a marker of cancer stem cells, and the percentage of CD44-positive cancer cells was significantly higher in high-grade ccRCCs (26.6%) than in low-grade ccRCCs (3.4%).

Furthermore, both the percentage of cells positive for CD44 and TNF-α correlated with pathological tumour stage, and co-upregulation of the two markers was significantly associated with pathological tumour stage as well as distant metastasis and Fuhrman nuclear grade.

In addition, patients with high TNF-α and CD44 protein expression had “dramatically worse” progression-free and overall survival than those with low expression, notes the team. Indeed, all patients with low TNF-α and CD44 expression were alive after 120 months of follow-up, compared with around 45% of those with high expression.

Similar results were observed for the 25 sunitinib-treated patients included in the study. In this subgroup, multivariate analysis revealed that TNF-α and CD44 expression, as well as Fuhrman nuclear grade, were independent prognostic factors for progression-free survival.

Moreover, residual carcinoma cells from sunitinib-treated metastatic ccRCC were strongly positive for CD44 staining whereas untreated cells were not, and CD44 expression was significantly higher in the tumours from the sunitinib-treated patients than in those from untreated ones.

The researchers also showed that treating ccRCC cell lines with TNF-α resulted in enhanced migration and invasion of tumour cells together with downregulation of E-cadherin expression and upregulation of matrix metalloproteinase 9 and CD44 expression. Importantly, TNF-α also upregulated the expression of TNF-α itself, they say.

“Our data show that TNF-α plays an important role in progression of ccRCCs by inducing [epithelial-to-mesenchymal transition] and CD44 expression, and suggest that CD44 induced by TNF-α may be involved in the resistance to the sunitinib treatment”, write Mikami and co-authors in the International Journal of Cancer.

They say that, in the future, TNF-α could be used as a predictive biomarker for sunitinib efficacy as well as a target molecule for the treatment of patients with metastatic ccRCC.

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