Roles of tumor suppressors in regulating tumor-associated inflammation

Abstract

Loss or silencing of tumor suppressors (TSs) promotes neoplastic transformation and malignant progression. To date, most work on TS has focused on their cell autonomous effects. Recent evidence, however, demonstrates an important noncell autonomous role for TS in the control of tumor-associated inflammation. We review evidence from clinical data sets and mouse model studies demonstrating enhanced inflammation and altered tumor microenvironment (TME) upon TS inactivation. We discuss clinical correlations between tumor-associated inflammation and inactivation of TS, and their therapeutic implications. This review sets forth the concept that TS can also suppress tumor-associated inflammation, a concept that provides new insights into tumor-host interactions. We also propose that in some cases the loss of TS function in cancer can be overcome through inhibition of the resulting inflammatory response, regardless whether it is a direct or an indirect consequence of TS loss.

Figure 1

TS regulate the inflammatory microenvironment: loss of TS (input, black arrows), including p53, TGFβ, APC, and PTEN, increases expression of growth factors, cytokines, and chemokines, which induce infiltration of host-derived inflammatory and stromal cells (mechanisms, in the big center circle). These cells in turn promote sustained proliferation, evasion of apoptosis, replicative immortality, dysregulation of metabolism, invasion, metastasis, and genomic instability (output, blue arrows)

Figure 2

Different mechanisms involving TME components contribute to T-cell tolerance and drug resistance in PCa. Androgen ablation in the TRAM mouse model induces cancer cell death/hypoxia and myofibroblast transdifferentiation (CAF). CAFs produce high levels of TGFβ and suppress host immunity by promoting Treg function and suppressing CTL activation. In addition, CAFs produce chemokines such as CXCL13, and recruit LT-producing B cells, a process dependent on TGFβ signaling in CAFs. Pro-tumorigenic B cells produce LT and immune-suppressive factors that have an important role in resistance of androgen ablation and chemotherapy

Figure 3

Tumor-associated inflammation is critical for converting TGFβ from a TS to a metastasis promoter. Host-derived immature myeloid Gr-1⁺CD11b⁺ cells are recruited into the TME upon deletion of Tgfbr2 in mammary carcinomas epithelial cells, through CXCL5:CXCR2 and SDF-1:CXCR4 interactions. In addition, Gr-1⁺CD11b⁺ cells express MMPs and TGFβ1, which promote tumor invasion and immune suppression. The effect of these immature myeloid cells on the TME and host immune surveillance promotes metastatic spread and is an essential contributor to the pro-metastatic action of TGFβ

Figure 4

Targeting opportunities aimed at inflammation and the TME in case of TS loss. IKKβ or IKKα inhibitors, metformin, as well as anti-inflammation drugs can be used with conventional chemotherapeutic agents, radiation therapies, and targeted therapies. In addition, neutralization antibodies, antagonists, and cell type-specific targeting may offer additional options to inhibit the inflammatory TME and enhance host antitumor immunity