Tumor Milieu Controlled by RB Tumor Suppressor

Abstract

The RB gene is one of the most frequently mutated genes in human cancers. Canonically, RB exerts its tumor suppressive activity through the regulation of the G1/S transition during cell cycle progression by modulating the activity of E2F transcription factors. However, aberration of the RB gene is most commonly detected in tumors when they gain more aggressive phenotypes, including metastatic activity or drug resistance, rather than accelerated proliferation. This implicates RB controls’ malignant progression to a considerable extent in a cell cycle-independent manner. In this review, we highlight the multifaceted functions of the RB protein in controlling tumor lineage plasticity, metabolism, and the tumor microenvironment (TME), with a focus on the mechanism whereby RB controls the TME. In brief, RB inactivation in several types of cancer cells enhances production of pro-inflammatory cytokines, including CCL2, through upregulation of mitochondrial reactive oxygen species (ROS) production. These factors not only accelerate the growth of cancer cells in a cell-autonomous manner, but also stimulate non-malignant cells in the TME to generate a pro-tumorigenic niche in a non-cell-autonomous manner. Here, we discuss the biological and pathological significance of the non-cell-autonomous functions of RB and attempt to predict their potential clinical relevance to cancer immunotherapy.

Oncolytic Adenovirus: Prospects for Cancer Immunotherapy

“…E1A gene conserved region 2 (CR2) encodes E1A protein sequence which can bind to and inactivate retinoblastoma (Rb) proteins ( Heise et al, 2000 ). The Rb protein is considered to be a tumor suppressor, which functions through binding to E2F and thus inhibiting cell cycle progression ( Kitajima et al, 2020 ). E2F acts as a transcriptional activator to regulate expression of key genes that enable the quiescent cells to enter into S-phase ( Kent and Leone, 2019 ).…”

Targeting RB1 Loss in Cancers

“…As alluded to the introduction, mostly in an E2F-dependent manner, RB1 status affects the milieu surrounding tumor cells including chemokine/cytokine secretion, extracellular matrix, immune cells or remote organs to be metastasized. The molecules mediating such functions of RB1 could serve as good therapeutic targets [37,38]. C-C motif chemokine 2 (CCL2) appeared to be secreted from RB1-deficient breast cancer cells, thereby such tumor cells recruit immunosuppressive cells including myeloid-derived suppressive cells (MDSC), regulatory T cells (Treg) or macrophages, allowing malignant progression following RB1 inactivation.…”

“…C-C motif chemokine 2 (CCL2) appeared to be secreted from RB1-deficient breast cancer cells, thereby such tumor cells recruit immunosuppressive cells including myeloid-derived suppressive cells (MDSC), regulatory T cells (Treg) or macrophages, allowing malignant progression following RB1 inactivation. Moreover, blockade of CCL2 signaling in host mice by genetically deleting CCR2, encoding the receptor for CCL2, almost completely abrogated mammary carcinogenesis from MMTV-cre; Rb1 flox/flox mice [14,38]. RB1 inactivation has been linked to upregulation of PD-L1 expression through direct interaction with NF-κB protein p65.…”

Tumor-specific lytic path “hyperploid progression mediated death”: Resolving side effects through targeting retinoblastoma or p53 mutant

“…Nevertheless, the exact molecular mechanism through which Rb executes G1 arrest remains incompletely understood[ 36 ]. The binding of Rb to DNA-affinity columns suggested that Rb’s intracellular function may be regulatory in nature, which was confirmed by its role in regulating gene transcription[ 4 , 37 , 38 ].…”