Cancer cell-intrinsic properties caused by oncogenic mutations have been well characterized; however, how specific oncogenes and tumor suppressors impact the tumor microenvironment (TME) is not well understood. Here, we present a novel non-cell-autonomous function of the retinoblastoma (RB) tumor suppressor in controlling the TME. RB inactivation stimulated tumor growth and neoangiogenesis in a syngeneic and orthotropic murine soft-tissue sarcoma model, which was associated with recruitment of tumor-associated macrophages (TAM) and immunosuppressive cells such as Gr1 þ CD11b þ myeloid-derived suppressor cells (MDSC) or Foxp3 þ regulatory T cells (Treg). Gene expression profiling and analysis of genetically engineered mouse models revealed that RB inactivation increased secretion of the chemoattractant CCL2. Furthermore, activation of the CCL2-CCR2 axis in the TME promoted tumor angiogenesis and recruitment of TAMs and MDSCs into the TME in several tumor types including sarcoma and breast cancer. Loss of RB increased fatty acid oxidation (FAO) by activating AMP-activated protein kinase that led to inactivation of acetyl-CoA carboxylase, which suppresses FAO. This promoted mitochondrial superoxide production and JNK activation, which enhanced CCL2 expression. These findings indicate that the CCL2-CCR2 axis could be an effective therapeutic target in RB-deficient tumors. Significance: These findings demonstrate the cellnonautonomous role of the tumor suppressor retinoblastoma in the tumor microenvironment, linking retinoblastoma loss to immunosuppression.

Retinoblastoma tumor suppressor protein (RB) is inactivated more frequently during tumor progression than during tumor initiation. However, its exact role in controlling the malignant features associated with tumor progression is poorly understood. We established in vivo and in vitro models to investigate the undifferentiated state induced by Rb inactivation. Rb heterozygous mice develop well-differentiated thyroid medullary carcinoma. We found that additional deletion of Trp53, without change in lineage, converted these Rb-deficient tumors to a poorly differentiated type associated with higher self-renewal activity. Freshly prepared mouse embryonic fibroblasts (MEFs) of Rb 2/2 ; Trp53 2/2 background formed stem cell-like spheres that expressed significant levels of embryonic genes despite of lacking the ability to form colonies on soft agar or tumors in immune-deficient mice. This suggested that Rb-p53 double inactivation resulted in an undifferentiated status but without carcinogenic conversion. We next established Rb 2/2 ; N-ras 2/2 MEFs that harbored a spontaneous carcinogenic mutation in Trp53. These cells (RN6), in an Rb-dependent manner, efficiently generated spheres that expressed very high levels of embryonic genes, and appeared to be carcinogenic. We then screened an FDA-approved drug library to search for agents that suppressed the spherogenic activity of RN6 cells. Data revealed that RN6 cells were sensitive to specific agents including ones those are effective against cancer stem cells. Taken together, all these findings suggest that the genetic interaction between Rb and p53 is a critical determinant of the undifferentiated state in normal and tumor cells.

As a common geological hazard, land subsidence is widely distributed in the Eastern Beijing Plain. The pattern of evolution of this geological phenomenon is controlled by many factors, including groundwater level change in different aquifers, compressible layers of different thicknesses, and static and dynamic loads. First, based on the small baseline subset Interferometric Synthetic Aperture Radar (SBAS-InSAR) technique, we employed 47 ENVISAT ASAR images and 48 RADARSAT-2 images to acquire the ground deformation of the Beijing Plain from June 2003 to November 2015 and then validated the results using leveling benchmark monitoring. Second, we innovatively calculated additional stress to obtain static and dynamic load information. Finally, we evaluated the contribution rate of the influencing factors to land subsidence by using the Spearman’s rank correlation coefficient (SRCC) and extremely randomized trees (ERT) machine learning methods. The SBAS-InSAR outcomes revealed that the maximum deformation rate was 110.7 mm/year from 2003 to 2010 and 144.4 mm/year from 2010 to 2015. The SBAS-InSAR results agreed well with the leveling benchmark monitoring results; the correlation coefficients were 0.97 and 0.96 during the 2003–2010 and 2013–2015 periods, respectively. The contribution rate of the second confined aquifer to the cumulative land subsidence was 49.3% from 2003 to 2010, accounting for the largest proportion; however, its contribution rate decreased to 23.4% from 2010 to 2015. The contribution rate of the third confined aquifer to the cumulative land subsidence increased from 2003 to 2015. Although the contribution of additional stress engendered from static and dynamic loads to the cumulative land subsidence was slight, it had a significant effect on the uneven land subsidence, with a contribution rate of 33.8% from 2003 to 2010 and 23.1% from 2010 to 2015. These findings provide scientific support for mitigating hazards associated with land subsidence.

Cancer stem cells (CSCs) refer to a subpopulation of cancer cells responsible for tumorigenesis, metastasis, and drug resistance. Increasing evidence suggests that CSC-associated tumor neovascularization partially contributes to the failure of cancer treatment. In this review, we discuss the roles of CSCs on tumor-associated angiogenesis via trans-differentiation or forming the capillary-like vasculogenic mimicry, as well as the roles of CSCs on facilitating endothelial cell-involved angiogenesis to support tumor progression and metastasis. Furthermore, we discuss the underlying regulation mechanisms, including the intrinsic signals of CSCs and the extrinsic signals such as cytokines from the tumor microenvironment. Further research is required to identify and verify some novel targets to develop efficient therapeutic approaches for more efficient cancer treatment through interfering CSC-mediated neovascularization.