Effect of Tumor Burden on Tumor Aggressiveness and Immune Modulation in Prostate Cancer: Association with IL-6 Signaling

Abstract

Local treatment is known to improve survival in men with locally advanced prostate cancer (LAPC), but the underlying mechanisms remain unclear. In the present study, we examined the role of tumor burden in tumor aggressiveness, as well as the pathway responsible for these changes. We used human and murine prostate cancer cell lines to examine the role of tumor burden in tumor aggressiveness, as well as its correlation with cancer stem cell (CSC) marker levels and IL-6 signaling. Furthermore, 167 prostate cancer biopsy specimens were analyzed in terms of correlations of IL-6 and CD44 levels with clinical patient characteristics. Data from preclinical models showed that larger tumor burden was associated with more aggressive tumor growth associated and increased CD44 expression. Using cellular experiments and orthotopic tumor models, we showed that CD44+ prostate cancer cells have CSC-like properties, enhanced epithelial–mesenchymal transition (EMT), and a more immunosuppressive microenvironment. There was a significant correlation between IL-6 and CD44 levels based on in vitro testing of clinical samples. Blockade of IL-6/STAT3 signaling attenuated the expression of CD44, CSC-like properties, and aggressive tumor behavior in vitro and in vivo. In conclusion, CD44 expression is significantly associated with tumor aggressiveness in prostate cancer and activation of IL-6 signaling leads to a suitable microenvironment for the induction of CD44 expression. Based on our study, reduced tumor burden was associated with attenuated IL-6 signaling and augmented tumor rejection in the microenvironment, which might mediate the benefit of clinical adoption with aggressive local therapy.

CD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3

“…In turn, well known STAT3 activators IL-6 ( 84 ) and IGF-1 ( 85 ) have been shown to significantly induce CD44 promoter activity in pancreatic tumor cells ( 12 ), while in hepatocytes several putative STAT3 binding sites have been described within the CD44 promoter, demonstrating that STAT3 can directly induce CD44 expression ( 86 ). In line with these observations, STAT3 blockade via siRNA or specific inhibitors has been reported to significantly decrease CD44 expression in breast, prostate, nasopharyngeal, and gastric carcinoma models ( 77 , 78 , 80 , 81 , 87 , 88 ). Collectively, these results show that CD44 and STAT3 can regulate each other’s expression and cooperate across different tumor types to drive cancer invasion, metastasis, disease recurrence, and chemoresistance.…”

“…Furthermore, numerous studies indicate that CD44 and STAT3 regulate each other’s expression and activity. In prostate cancer, CD44 expression significantly correlates with IL-6, a STAT3-activating cytokine, and IL-6 or STAT3 inhibition both decrease CD44 and EMT-related protein levels in cancer cell lines ( 77 , 78 ). In agreement with these observations, monoclonal antibodies targeting the CD44s isoform reduce CSC percentage in cultured pancreatic cancer cells and in xenograft mouse models, along with downregulating STAT3 levels and STAT3-mediated target gene expression ( 79 ).…”

Immune evasion by cancer stem cells

“…C/EBPδ also mediated IL-6- and hypoxia-induced breast CSCs by activating the NOTCH1 pathway [ 140 ]. In prostate cancer, IL-6 induced CD44 + CSCs in an autocrine manner [ 141 ]. IL-6 and CD44 expression was significantly associated with tumor malignancy and poor prognosis [ 141 ].…”

“…In prostate cancer, IL-6 induced CD44 + CSCs in an autocrine manner [ 141 ]. IL-6 and CD44 expression was significantly associated with tumor malignancy and poor prognosis [ 141 ]. IL-6 also upregulated PD-L1 expression in CD44 + CSCs and recruited MDSCs to tumors and suppressed tumor infiltration of T cells [ 141 ].…”

“…IL-6 and CD44 expression was significantly associated with tumor malignancy and poor prognosis [ 141 ]. IL-6 also upregulated PD-L1 expression in CD44 + CSCs and recruited MDSCs to tumors and suppressed tumor infiltration of T cells [ 141 ]. Inhibition of the IL-6/STAT3 pathway resulted in the downregulation of PD-L1 and CD44 expression, decreased CSC properties, and suppressed tumor growth [ 141 ].…”