The Bladder Tumor Microenvironment Components That Modulate the Tumor and Impact Therapy

Abstract

The tumor microenvironment (TME) is complex and involves many different cell types that seemingly work together in helping cancer cells evade immune monitoring and survive therapy. The advent of single-cell sequencing has greatly increased our knowledge of the cell types present in the tumor microenvironment and their role in the developing cancer. This, coupled with clinical data showing that cancer development and the response to therapy may be influenced by drugs that indirectly influence the tumor environment, highlights the need to better understand how the cells present in the TME work together. This review looks at the different cell types (cancer cells, cancer stem cells, endothelial cells, pericytes, adipose cells, cancer-associated fibroblasts, and neuronal cells) in the bladder tumor microenvironment. Their impact on immune activation and on shaping the microenvironment are discussed as well as the effects of hypertensive drugs and anesthetics on bladder cancer.

Keywords: bladder cancer; single cells; tumor microenvironment.

Figure 1

The Tumor Microenvironment.

Figure 2

The dynamic action of different cell types that produce the mature TME.The diverse cells present in the TME influence one another, which contributes to tumor growth and prognosis. The outgoing arrows indicate the release of soluble molecules from different cells that impact the target cells within the TME. BC cells propagate their own proliferation and migration (metastasis) through autocrine signaling pathways, involving the production of tumor-promoting and pro-inflammatory cytokines such as IL-6, TNF, and IL-1. BC cells secrete EVs, which can further activate tumor cells in a positive loop and induce tumor cell metastasis, especially through the delivery of non-coding RNAs. Tumor-derived EVs also fuel an immunosuppressive environment by recruiting and activating tumor-infiltrating fibroblasts. These CAFs and pro-tumorigenic immune cells, such as MDSCs and TAMs, are recruited to the TME by the cytokines and chemokines secreted by the BC cells. Once in the TME, these cells provide feedback to the tumor cells by secreting soluble molecules and also inactivate other immune cells, such as T-cells, by upregulating the expression of exhaustion markers. BC cells also recruit and activate endothelial cells (angiogenesis) through the secretion of soluble factors such as IL-1, IL-8, and VEGF, as well as long intergenic non-coding RNAs such as LINC00482. These activated endothelial cells form disorganised networks of blood vessels, which are leaky and supply the tumor cells with life-sustaining nutrients. Endothelial cells, adipocytes, and neurons, in turn, influence the tumor cells by secreting inflammatory cytokines, chemokines, growth factors, hormones, and other signaling peptides.