Infiltrating T Cells Promote Bladder Cancer Progression via Increasing IL1→Androgen Receptor→HIF1α→VEGFa Signals

Abstract

The tumor microenvironment impacts tumor progression and individual cells, including CD4+ T cells, have been detected in bladder cancer (BCa) tissues. The detailed mechanism how these T cells were recruited to the BCa tumor and their impact on BCa progression, however, remains unclear. Using a human clinical BCa sample survey and in vitro co-culture system, we found that BCa has a greater capacity to recruit T cells than surrounding normal bladder tissues. The consequences of higher levels of recruited T cells in BCa included increased BCa metastasis. Mechanism dissection revealed that infiltrating T cells might function through secreting the cytokine IL-1 which increases the recruitment of T cells to BCa and enhances the BCa androgen receptor (AR) signaling that results in increased BCa cell invasion via up-regulation of HIF-1α/VEGFa expression. Interruption of the IL-1→AR→HIF-1α→VEGFa signals with inhibitors of HIF-1α or VEGFa partially reversed the enhanced-BCa cell invasion. Finally, in vivo mouse models of xenografted BCa T24 cells with CD4+ T cells confirmed in vitro co-culture studies and concluded that infiltrating CD4+ T cells can promote BCa metastasis via modulation of the IL-1→AR→HIF-1α→VEGFa signaling. Future clinical trials using small molecules to target this newly identified signaling pathway may facilitate the development of new therapeutic approaches to better suppress BCa metastasis.

Identification and Validation of an Individualized Prognostic Signature of Bladder Cancer Based on Seven Immune Related Genes

“…To further elucidate the role of tumor milieu associated with the 7-IRG signature, we analyzed the estimations of six types of immune cells and observed increased abundance of CD4+ T cells, CD8+ T cells, macrophage, neutrophil and dendritic cells in the high-risk group. T cells infiltration was reported to promote tumor invasion and metastasis via the androgen receptor (Tao et al, 2016) and estrogen receptor signaling (Tao et al, 2018) among BLCA patients. This aspect aligned with a clinical study that demonstrated the prognostic role of a specific subset of CD4+ T cells (Th17) (Chugh et al, 2013).…”

Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3

“…PHF8 knockdown arrests the cell cycle at G0/G1 [17], and could thereby reduce the level of phosphorylated AKT, which is known to be critical for HIF1α stability [40,41]. This potential link may also explain the mechanism underlying the association of PHF8-mediated regulation of HIF1α with AR status in prostate cancer cells, in part because, activated AR signaling can activate HIF1α through autocrine loop involving EGF/PI3K/PKB [7] or directly through transcriptional regulation [42]. Additional supporting evidence is the recently identified HIF/PHF8/AR axis, in which PHF8 regulates AR target genes under hypoxia [18], thus, it is also possible that PHF8 indirectly regulates HIF1A through AR signaling.…”

Bladder Urothelial Carcinoma with Peritoneal Involvement: Benefit of Continuous Maintenance Chemotherapy

“…The tumor microenvironment has been shown to affect tumor progression, and has been detected in bladder cancer tissues (32). Evidence suggests that critical elements of the tumor microenvironment are immune and inflammatory cells, blood and lymphatic vascular networks, fibroblasts, and the extracellular matrix (33).…”