Reactive stroma initiates during early prostate cancer development and coevolves with prostate cancer progression. Previous studies have defined the key markers of reactive stroma and have ...established that reactive stroma biology influences prostate tumorigenesis and progression. The stem/progenitor cells of origin and the mechanisms that regulate their recruitment and activation to myofibroblasts or carcinoma-associated fibroblasts are essentially unknown. Key regulatory factors have been identified, including transforming growth factor β, interleukin-8, fibroblast growth factors, connective tissue growth factor, wingless homologs-Wnts, and stromal cell-derived factor-1, among others. The biology of reactive stroma in cancer is similar to the more predictable biology of the stroma compartment during wound repair at sites where the epithelial barrier function is breached and a stromal response is generated. The coevolution of reactive stroma and the biology of how reactive stroma-carcinoma interactions regulate cancer progression and metastasis are targets for new therapeutic approaches. Such approaches are strategically designed to inhibit cancer progression by uncoupling the reactive stroma niche.
This paper discusses the framework for comparing independent study means (SMs) with averages of aggregated study mean paleomagnetic poles, hereafter referred to as reference poles, contributing to ...continental or global apparent polar wander paths (GAPWP). Paleomagnetists typically compare individual SMs to these population means to compute latitudinal displacements or rotations with uncertainties estimated by comparing A95's. Using this comparison statistic, more than half of the population of reference SMs contributing to a GAPWP fall at an angular distance that is greater than their combined uncertainties. Two approaches are presented that yield similar results based on different rationales and comparison statistics. Common to both approaches is K95,GAPWP, the angular distance within which 95% of poles contributing to an APWP mean fall. One approach combines K95,GAPWP and the A95,SM of the independent study mean that can only be judged to be significantly displaced if the angular difference with the GAPWP mean exceeds their combined uncertainty. The second approach uses K95,GAPWP as the best estimate of total error of each study mean, which when combined with uncertainty of the GAPWP mean, A95,GAPWP, defines the angular difference that the independent study mean needs to exceed to be judged to be significantly displaced from a GAPWP mean. These comparison statistics are used to assess paleomagnetic support for Greater Indian Basin hypothesis for the paleogeographic evolution of the northern margin of India prior to collision with Asia. The Greater Indian Basin hypothesis is not supported based on these more rigorous criteria.
Key Points
Approximately 55% of study means contributing to global apparent polar wander paths (APWP) are more distant from interval mean poles than the combined uncertainty
Study means contributing to global APWPs are Fisher distributed with a mean VGP dispersion parameter, K of 90 implying that unrecognized errors contribute significantly to dispersion of study means global APWP
Individual study mean poles should be compared with APWPs using K95 or more conservatively G95 not A95 of the APWP, thus limiting the resolution of such comparisons
•We report lacustrine carbonate δ18O from three basins in SE Tibet and Yunnan.•Basin paleoelevation was model-based calculated from δ18O.•SE Yunnan reached its current elevation (∼1.6 km) by ∼13 ...Ma.•Lower crustal flow in SE Yunnan occurred >13 Ma.
An improved understanding of the elevation history of the Tibetan Plateau is crucial in discriminating among the various tectonic models for the evolution of the India–Asia continental collision. We reconstruct the paleoelevation history for three Cenozoic sedimentary basins from SE Tibet and Yunnan, China, to provide more constraints on the tectonic processes for raising the SE margin of the Tibetan Plateau. The results presented here, together with those of previous studies, indicate that (1) the plateau margin of NW Yunnan was near its elevation (∼2.6 km) by the latest middle Eocene (∼40 Ma); (2) the plateau margin of SE Yunnan reached its current elevation (∼1.6 km) by the middle Miocene (∼13 Ma). Interpretations of the tectonic processes responsible for this inferred surface uplift of the region are made in the context of well-documented surface geology. We conclude that high landscape (∼2.6 km elevation) in NW Yunnan may represent the remnants of the Eocene Tibetan plateau that originally formed in the northeastern Qiangtang Block by crustal thickening associated with the India–Asia continental collision. The near-modern elevation of SE Yunnan since ∼13 Ma probably reflects the initiation of lower crustal flow in this area by at least that time. Collectively, our paleoaltimetric interpretations disagree with previously proposed models of middle Miocene to Pliocene crustal flow acting as a sole tectonic process for raising the SE margin of the plateau, but support a protracted history of surface uplift that most likely involved crustal thickening during the Eocene, southeastward extrusion of a portion of Eocene Tibetan plateau during the Oligocene to early Miocene, and lower crustal flow beneath this region since at least the early Miocene.
The elevation history of the Tibetan plateau provides direct insight into the tectonic processes associated with continent-continent collisions. Here we present oxygen-isotope-based estimates of the ...palaeo-altimetry of late Eocene and younger deposits of the Lunpola basin in the centre of the plateau, which indicate that the surface of Tibet has been at an elevation of more than 4 kilometres for at least the past 35 million years. We conclude that crustal, but not mantle, thickening models, combined with plate-kinematic solutions of India-Asia convergence, are compatible with palaeo-elevation estimates across the Tibetan plateau.
Earth's topography arises from the linear superposition of isostatic and dynamic contributions. The isostatic contribution reflects the distribution of thickness and density of the crust overlying a ...static, non‐convecting mantle. We argue that isostatic topography should be limited to the crust, thereby delimiting all sources for dynamic topography below the Moho. Dynamic topography is the component of the topography produced by normal stresses acting on the Moho that deflect the isostatic topography away from crustal isostatic equilibrium largely as a consequence of mantle flow dynamics. These normal stresses arise from pressure variations and vertical gradients of the radial flow in the convecting mantle. The best estimate of dynamic topography is from the residual topography, which is the difference between observed topography and crustal isostatic topography. Dynamic and residual topography are the same. It is clear that thermal anomalies horizontally advected by plate motions would not exist if the mantle were not convecting, therefore their contribution to topography is inherently dynamic in origin. The global integral of dynamic topography that encompasses all non‐crustal buoyancy sources is demonstrated to be equal to zero. It follows that mantle convection cannot change the mean radius or mean elevation of the Earth. Since changes in ocean basin volume driven by changes in mean depth of the oceans are inherently part of dynamic topography, thereby requiring that continental elevations must also change, such that the global integral of these perturbations must also be equal to zero. This constraint has important implications for global long‐term sea level and the stratigraphic record, among other features of the Earth system impacted by changes in Earth's dynamic topography.
Key Points
Earth's topography arises from the linear superposition of crustal isostatic and dynamic contributions
The global integral of dynamic topography that encompasses all non‐crustal buoyancy sources equals zero
The best estimate of Earth's dynamic topography is the difference between observed and crustal isostatic topography
A recent article in Cell shows that vitamin D receptor activation reprograms reactive stroma in the tumor microenvironment to a less inflammatory, quiescent state and is associated with increased ...drug retention, tumor response, and survival in pancreatic cancer models. Stroma reprogramming, as opposed to ablation, may emerge as a new treatment paradigm.
A recent article in Cell shows that vitamin D receptor activation reprograms reactive stroma in the tumor microenvironment to a less inflammatory, quiescent state and is associated with increased drug retention, tumor response, and survival in pancreatic cancer models. Stroma reprogramming, as opposed to ablation, may emerge as a new treatment paradigm.
Commensal bifidobacteria colonize the human gastrointestinal tract and catabolize glycans that are impervious to host digestion. Accordingly,
typically secretes acetate and lactate as fermentative ...end products. This study tested the hypothesis that
utilizes cranberry-derived xyloglucans in a strain-dependent manner. Interestingly, the
strain that efficiently utilizes cranberry xyloglucans secretes 2.0 to 2.5 mol of acetate-lactate. The 1.5 acetate:lactate ratio theoretical yield obtained in hexose fermentations shifts during xyloglucan metabolism. Accordingly, this metabolic shift is characterized by increased acetate and formate production at the expense of lactate. α-l-Arabinofuranosidase, an arabinan endo-1,5-α-l-arabinosidase, and a β-xylosidase with a carbohydrate substrate-binding protein and carbohydrate ABC transporter membrane proteins are upregulated (>2-fold change), which suggests carbon flux through this catabolic pathway. Finally, syntrophic interactions occurred with strains that utilize carbohydrate products derived from initial degradation from heterologous bacteria.
This was a study of bacterial metabolism of complex cranberry carbohydrates termed xyloglucans that are likely not digested prior to reaching the colon. This is significant, as bifidobacteria interact with this dietary compound to potentially impact human host health through energy and metabolite production by utilizing these substrates. Specific bacterial strains utilize cranberry xyloglucans as a nutritive source, indicating unknown mechanisms that are not universal in bifidobacteria. In addition, xyloglucan metabolism proceeds by using an alternative pathway that could lead to further research to investigate mechanisms underlying this interaction. Finally, we observed cross-feeding between bacteria in which one strain degrades the cranberry xyloglucan to make it available to a second strain. Similar nutritive strategies are known to occur within the gut. In aggregate, this study may lead to novel foods or supplements used to impact human health through rational manipulation of the human microbiome.
Significance Recruitment, proliferation, and differentiation of myofibroblasts are common in many disease states. Mechanisms that regulate proliferation and differentiation are poorly understood, ...although TGF-β is a key inducer of differentiation. Here, we report, for the first time to our knowledge, that runt-related transcription factor 1 (RUNX1) regulates mesenchymal stem cell (MSC) biology and progenitor cell commitment to myofibroblasts. In this work, we describe the first identification, to our knowledge, of tissue-resident MSCs from adult normal human prostate gland and the role of these MSCs as myofibroblast precursors. We also pinpoint the role of RUNX1 in regulating proliferation and differentiation in both marrow-derived and tissue-resident MSCs. Perturbation of RUNX1 activity may provide insights for developing antifibrotic and anticancer therapies via targeting the reactive stroma microenvironment.
Myofibroblasts are a key cell type in wound repair, cardiovascular disease, and fibrosis and in the tumor-promoting microenvironment. The high accumulation of myofibroblasts in reactive stroma is predictive of the rate of cancer progression in many different tumors, yet the cell types of origin and the mechanisms that regulate proliferation and differentiation are unknown. We report here, for the first time to our knowledge, the characterization of normal human prostate-derived mesenchymal stem cells (MSCs) and the TGF-β1–regulated pathways that modulate MSC proliferation and myofibroblast differentiation. Human prostate MSCs combined with prostate cancer cells expressing TGF-β1 resulted in commitment to myofibroblasts. TGF-β1–regulated runt-related transcription factor 1 (RUNX1) was required for cell cycle progression and proliferation of progenitors. RUNX1 also inhibited, yet did not block, differentiation. Knockdown of RUNX1 in prostate or bone marrow-derived MSCs resulted in cell cycle arrest, attenuated proliferation, and constitutive differentiation to myofibroblasts. These data show that RUNX1 is a key transcription factor for MSC proliferation and cell fate commitment in myofibroblast differentiation. This work also shows that the normal human prostate gland contains tissue-derived MSCs that exhibit multilineage differentiation similar to bone marrow-derived MSCs. Targeting RUNX1 pathways may represent a therapeutic approach to affect myofibroblast proliferation and biology in multiple disease states.
Stromal cells in the tumor microenvironment regulate the immune landscape and tumor progression. Yet, the ontogeny and heterogeneity of reactive stromal cells within tumors is not well understood. ...Carcinoma-associated fibroblasts exhibiting an inflammatory phenotype (iCAFs) have been identified within multiple cancers; however, mechanisms that lead to their recruitment and differentiation also remain undefined. Targeting these mechanisms therapeutically may be important in managing cancer progression. Here, we identify the ELF3 transcription factor as the canonical mediator of IL-1α-induced differentiation of prostate mesenchymal stem cells to an iCAF phenotype, typical of the tumor microenvironment. Furthermore, IL-1α-induced iCAFs were subsequently refractive to TGF-β1 induced trans-differentiation to a myofibroblast phenotype (myCAF), another key carcinoma-associated fibroblast subtype typical of reactive stroma in cancer. Restricted trans-differentiation was associated with phosphorylation of the YAP protein, indicating that interplay between ELF3 action and activation of the Hippo pathway are critical for restricting trans-differentiation of iCAFs. Together, these data show that the IL-1α/ELF3/YAP pathways are coordinate for regulating inflammatory carcinoma-associated fibroblast differentiation.
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