The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
David R Rowley - One of the best experts on this subject based on the ideXlab platform.
-
Role of Reactive Stroma in Prostate Cancer
Prostate Cancer, 2013Co-Authors: Rebeca San Martin, David R RowleyAbstract:Reactive Stroma initiates at sites of epithelial damage to mediate tissue repair and restore homeostasis. Genomic instability of epithelial cells at sites of early lesions such as prostatic intraepithelial neoplasia produces a similar breach of the epithelial barrier and an initiation of reactive Stroma. Reactive Stromal cells, termed myofibroblasts and carcinoma-associated fibroblasts, have been shown to originate potentially from several sources including tissue fibroblasts, resident Stromal stem cells, vascular cells, and marrow-derived mesenchymal stem cells. Several growth factors such as transforming growth factor-β and interleukin-8 induce reactive Stroma and regulate several downstream factors expressed in reactive Stroma. Reactive Stroma in prostate cancer is heterogeneous, and the amount of reactive Stroma is predictive of disease progression. The heterogeneity of cells in reactive Stroma is possibly a key aspect of the tumor-promoting properties. It is likely that reactive Stroma biology is an important aspect of tumor progression to metastasis and acquired therapeutic resistance. Targeting the tumor microenvironment reactive Stroma together with direct targeting of cancer cells may represent an effective therapeutic approach for the treatment of prostate cancer.
-
the reactive Stroma microenvironment and prostate cancer progression
Endocrine-related Cancer, 2012Co-Authors: David Barron, David R RowleyAbstract:Reactive Stroma initiates during early prostate cancer development and co-evolves 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 beta, 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 co-evolution 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.
-
stromogenic prostatic carcinoma pattern carcinomas with reactive Stromal grade 3 in needle biopsies predicts biochemical recurrence free survival in patients after radical prostatectomy
Human Pathology, 2007Co-Authors: Nobuyuki Yanagisawa, David R Rowley, Thomas M Wheeler, Rile Li, Dov Kadmon, Brian J Miles, Gustavo AyalaAbstract:Summary We previously reported that reactive Stromal grading in radical prostatectomies is a predictor of recurrence and that reactive Stromal grading 0 and 3 are associated with lower biochemical recurrence-free survival rates than reactive Stromal grading 1 and 2. We explored the prognostic significance of reactive Stromal grading in preoperative needle biopsies. At Baylor College of Medicine, 224 cases of prostatic carcinoma were diagnosed by needle biopsy. Reactive Stromal grading was evaluated on hematoxylin-eosin (HE grade 1, 6% to 15%; grade 2, 16% to 50%; grade 3, 51% to 100%, or at least a 1:1 ratio between glands and Stroma. Kaplan-Meier and Cox proportional hazard analyses were used. Reactive Stromal grading distribution was as follows: reactive Stromal grading 0, 1 case (0.5%); reactive Stromal grading 1, 149 cases (66.5%); reactive Stromal grading 2, 59 cases (26.3%); reactive Stromal grading 3, 15 cases (6.7%). Reactive Stromal grading in biopsies was correlated with adverse clinicopathologic parameters in the prostatectomy. Patients with reactive Stromal grading 1 and 2 had better survival than those with 0 and 3 ( P = .0034). Reactive Stromal grading was an independent predictor of recurrence (hazard ratio=1.953; P = .0174). Reactive Stromal grading is independent of Gleason 4 + 3 and 3 + 4 in patients with a Gleason score of 7. Quantitation of reactive Stroma and recognition of the stromogenic carcinoma in H&E-stained biopsies is useful to predict biochemical recurrence in prostate carcinoma patients independent of Gleason grade and prostate-specific antigen.
-
Reactive Stroma and tumor evolution
Cancer Research, 2005Co-Authors: David R Rowley, Jennifer A Tuxhorn, Feng Yang, Steven J. Ressler, Stephanie J. Mcalhany, Doug Strand, Isaiah G. Schauer, Dang D. DangAbstract:SY12-2 Our previous studies have shown that reactive Stroma in prostate cancer is characterized by progressive changes in Stromal cell phenotype from differentiated smooth muscle to an activated myofibroblast / fibroblast population. Reactive Stromal cells also exhibit elevated synthesis of pro-collagen I, tenascin, and fibroblast activation protein (FAP). In addition, we have shown that reactive Stroma originates immediately adjacent to premalignant prostatic intraepithelial neoplasia (PIN) foci in human prostate cancer. Many PIN foci also overexpress TGF-β1 suggesting this factor is a mediator of reactive Stroma. In addition to stimulating Stromal cell wound repair responses, TGF-β1 functions to stimulate angiogenesis by regulating endothelial-pericyte interactions, differentiation of pericytes, and vessel stability. Moreover, TGF-β1 regulates expression of Stromal growth factors important to wound repair Stroma and angiogenesis, including connective tissue growth factor (CTGF) and fibroblast growth factor-2 (FGF-2). Reactive Stroma in human PIN and cancer is associated with both elevated microvessel density and FGF-2 expression. Together, these data suggest that TGF-β1 and downstream regulators are critical for reactive Stroma biology and angiogenesis in the premalignant PIN cancer microenvironment. A central hypothesis is that epithelial overexpression of TGF-β1 in PIN induces a typical Stromal wound repair response via both direct and indirect actions mediated through downstream factors such as FGF-2. This Stromal response continues to co-evolve with the foci of epithelial carcinoma cells during cancer progression. It is likely that the co-evolution of a proper reactive Stroma is required for organ-confined progression of the carcinoma. Accordingly, it is becoming clearer that the reactive Stroma microenvironment is an important component of overall tumorigenesis and is likely to involve a complex interplay and feedback loops between key Stromal growth factors. We have developed the differential reactive Stroma (DRS) xenograft model to address the role of reactive Stroma, TGF-β1, CTGF and FGF-2 in prostate cancer. Differential tumorigenesis and angiogenesis was observed using different human prostate Stromal cell lines co-inoculated with LNCaP human prostate cancer cells into nude mice. The inclusion of either human or mouse prostate Stromal cells with LNCaP cancer cells resulted in a rapid and consistent angiogenesis and tumorigenesis as compared to LNCaP xenografts without the inclusion of Stromal cells. Inoculated Stromal cells were localized in reactive Stroma of resulting tumor and were also observed in the vessel wall in a perictye position, suggesting a direct role in angiogenesis. Gene expression analysis showed several TGF-β1 regulated genes (including CTGF) were differentially expressed in human prostate Stromal cells capable of supporting and promoting LNCaP xenograft tumors. Of interest, TGF-β1 was also shown to stimulate release of FGF-2 from prostate Stromal cells in vitro in a Smad3 dependent manner. Neutralization of TGF-β1 activity in xenograft LNCaP / Stromal cell tumors resulted in inhibited tumorigenesis and a significant (3.5 fold) reduction in microvessel density. Similarly, xenograft LNCaP tumors co-inoculated with TGF-β receptor II null or Smad3 dominant negative prostate Stromal cell lines resulted in significantly decreased tumorigenesis and angiogenesis. These data suggest that TGF-β1 is a key mediator of the immediate reactive Stroma microenvironment and functions directly and indirectly to stimulate epithelial tumorigenesis via actions in the Stromal compartment including the regulation of angiogenesis. To address the role of CTGF, FGF-2 and other TGF-β1 regulated genes, DRS tumors were constructed with Stromal cells engineered to overexpress genes of choice, either in a regulated manner (GeneSwitch) with Miphepristone (RU 486) or by transducing cells via retroviral infection. Prostate Stromal cells engineered to over express CTGF resulted in elevated tumorigenesis and a stimulation of angiogenesis during early LNCaP / Stromal cell xenograft tumor formation. Overexpression of FGF-2 in prostate Stromal cells resulted in an elevated Stromalization leading to fibrosis and differential tumor growth. Of interest, overexpression of FGF-2 in Stromal cells null for TGF-β receptor type II or positive for dominant negative Smad3, resulted in an overt Stromalization fibrosis that appeared to inhibit carcinoma cell survival in LNCaP / Stromal cell xenograft tumors. In addition, the overexpression or inclusion of recombinant ps20 (an additional TGF-β1 regulated gene) in Stromal cells resulted in increased tumorigenesis and angiogenesis. The ps20 protein also functioned to induce vascular cell adhesion molecule-1 (VCAM1) and induce the migration of human umbilical vein endothelial cells in vitro. These studies suggest that a principal function of carcinoma-expressed TGF-β1 in early prostate cancer is to induce a cascade of downstream regulatory factors in reactive Stroma, including CTGF, FGF-2, and ps20 which leads to a wound repair type of reactive Stroma response and induction of angiogenesis in the immediate tumor microenvironment. Our data suggests that the balanced actions of TGF-β1 and FGF-2 in the Stromal compartment may be what regulates the ratio of fibroblasts to myofibroblast cell types in carcinoma associated reactive Stroma. Moreover, it is appears that unbalanced action of FGF-2 in a Stromal environment that is restricted from TGF-β1 signaling, results in a non wound repair fibrosis type of Stromal response that might actually be tumor inhibitory. Together, these data suggest a complex feedback loop between TGF-β1 and FGF-2 signaling in tumor reactive Stroma and point to how significant the balanced Stromal response is to tumor progression. The reactive Stroma microenvironment might play a role in metastatic progression as well. A hallmark of more advanced prostate cancer progression is epithelial to mesenchymal transition (EMT) as evidenced by expression of mesenchymal markers and acquisition of a more migratory and invasive phenotype. These changes include a splice switch of the FGF receptor 2 IIIb to the IIIc isoform (FGFR2IIIc) and expression of FGF receptor 1 (FGFR1) in carcinoma cells. Both FGFR2IIIc and FGFR1 are cognate receptors for FGF-2. Carcinoma cells expressing these receptors would be expected to have a growth advantage in this reactive Stroma microenvironment, which is elevated in FGF-2 expression and possibly the release of FGF-2 protein. Accordingly, elevated FGF-2 in the adjacent reactive Stroma microenvironment might provide a selection advantage for carcinoma epithelial cells undergoing EMT and differential expression of these FGF receptors. This would be expected to lead to tumors that are composed of carcinoma cells expressing mesenchymal proteins with a more aggressive and invasive behavior. Together, these data suggest that reactive Stroma is important both in early progression of prostate cancer and during EMT changes, which ultimately lead to a Stromal-independent progression and metastasis. Our future studies will continue to be focused on dissecting key downstream signaling mechanisms and co-regulatory loops of TGF-β1, CTGF and FGF-2 action in reactive Stroma and carcinoma cell biology during prostate cancer progression.
-
reactive Stroma as a predictor of biochemical free recurrence in prostate cancer
Clinical Cancer Research, 2003Co-Authors: Gustavo Ayala, Jennifer A Tuxhorn, Thomas M Wheeler, Anna Frolov, Peter T Scardino, Makoto Ohori, Marcus Wheeler, Jeffrey Spitler, David R RowleyAbstract:Extensive scientific literature data point to reciprocal interactions between prostate Stromal cells and prostate cancer cells that likely regulate tumor progression. To investigate whether these intratumoral-reactive Stromal cells in human prostate cancer are predictive of survival, tumor Stroma volume and specific Stroma markers were quantitated by using tissue microarrays (index tumors of 847 patients), and the results were analyzed relative to the recurrence-free survival data set for these patients. Tumor tissue was evaluated with Masson’s trichrome stains and by immunohistochemistry with antibody probes to smooth muscle α-actin, desmin, vimentin, pro-collagen type I, and calponin. The relative volume of intratumor Stroma (5% Stroma, grade 0; 5–15%, grade 1; 15–50%, grade 2; >50%, grade 3) and the expression index of Stromal marker (staining intensity grade × percentage of positive cells per field) were quantitated and analyzed. Interpretable data were obtained from 545 patients. Statistical analysis of the survival data set showed that the volume of reactive Stroma in the tumor was a significant predictor of disease-free survival. Stroma volume was most optimal as an independent predictor in tumors containing Stroma, defined as Gleason 7 and lower grades. Of interest, tumors with either little to no Stroma or tumors with abundant Stroma each showed reduced recurrence-free survival. For specific Stromal markers, reduced desmin and smooth muscle α-actin were hallmarks of cancer-associated reactive Stroma relative to normal fibromuscular Stroma. Quantitative analysis of desmin and smooth muscle α-actin expression showed both to be significant and independent predictors of recurrence-free survival. This is the first study to demonstrate that nonepithelial-reactive Stroma elements in prostate cancer tumors can be used as prognostic indicators. These data also add to the concept that tumors are not purely epithelial and the tumor-reactive Stroma must be considered an important biological component of the cancer.
Gustavo Ayala - One of the best experts on this subject based on the ideXlab platform.
-
loss of caveolin 1 in prostate cancer Stroma correlates with reduced relapse free survival and is functionally relevant to tumour progression
The Journal of Pathology, 2013Co-Authors: Gustavo Ayala, Anna Frolov, Rile Li, Matteo Morello, Fabiana Rosati, Gianluca Bartolucci, Giovanna Danza, Rosalyn M Adam, Timothy C ThompsonAbstract:Levels of caveolin-1 (Cav-1) in tumour epithelial cells increase during prostate cancer progression. Conversely, Cav-1 expression in the Stroma can decline in advanced and metastatic prostate cancer. In a large cohort of 724 prostate cancers, we observed significantly decreased levels of Stromal Cav-1 in concordance with increased Gleason score (p = 0.012). Importantly, reduced expression of Cav-1 in the Stroma correlated with reduced relapse-free survival (p = 0.009), suggesting a role for Stromal Cav-1 in inhibiting advanced disease. Silencing of Cav-1 by shRNA in WPMY-1 prostate fibroblasts resulted in up-regulation of Akt phosphorylation, and significantly altered expression of genes involved in angiogenesis, invasion, and metastasis, including a > 2.5-fold increase in TGF-?1 and ?-synuclein (SNCG) gene expression. Moreover, silencing of Cav-1 induced migration of prostate cancer cells when Stromal cells were used as attractants. Pharmacological inhibition of Akt caused down-regulation of TGF-?1 and SNCG, suggesting that loss of Cav-1 in the Stroma can influence Akt-mediated signalling in the tumour microenvironment. Cav-1-depleted Stromal cells exhibited increased levels of intracellular cholesterol, a precursor for androgen biosynthesis, steroidogenic enzymes, and testosterone. These findings suggest that loss of Cav-1 in the tumour microenvironment contributes to the metastatic behaviour of tumour cells by a mechanism that involves up-regulation of TGF-?1 and SNCG through Akt activation. They also suggest that intracrine production of androgens, a process relevant to castration resistance, may occur in the Stroma.
-
stromogenic prostatic carcinoma pattern carcinomas with reactive Stromal grade 3 in needle biopsies predicts biochemical recurrence free survival in patients after radical prostatectomy
Human Pathology, 2007Co-Authors: Nobuyuki Yanagisawa, David R Rowley, Thomas M Wheeler, Rile Li, Dov Kadmon, Brian J Miles, Gustavo AyalaAbstract:Summary We previously reported that reactive Stromal grading in radical prostatectomies is a predictor of recurrence and that reactive Stromal grading 0 and 3 are associated with lower biochemical recurrence-free survival rates than reactive Stromal grading 1 and 2. We explored the prognostic significance of reactive Stromal grading in preoperative needle biopsies. At Baylor College of Medicine, 224 cases of prostatic carcinoma were diagnosed by needle biopsy. Reactive Stromal grading was evaluated on hematoxylin-eosin (HE grade 1, 6% to 15%; grade 2, 16% to 50%; grade 3, 51% to 100%, or at least a 1:1 ratio between glands and Stroma. Kaplan-Meier and Cox proportional hazard analyses were used. Reactive Stromal grading distribution was as follows: reactive Stromal grading 0, 1 case (0.5%); reactive Stromal grading 1, 149 cases (66.5%); reactive Stromal grading 2, 59 cases (26.3%); reactive Stromal grading 3, 15 cases (6.7%). Reactive Stromal grading in biopsies was correlated with adverse clinicopathologic parameters in the prostatectomy. Patients with reactive Stromal grading 1 and 2 had better survival than those with 0 and 3 ( P = .0034). Reactive Stromal grading was an independent predictor of recurrence (hazard ratio=1.953; P = .0174). Reactive Stromal grading is independent of Gleason 4 + 3 and 3 + 4 in patients with a Gleason score of 7. Quantitation of reactive Stroma and recognition of the stromogenic carcinoma in H&E-stained biopsies is useful to predict biochemical recurrence in prostate carcinoma patients independent of Gleason grade and prostate-specific antigen.
-
reactive Stroma as a predictor of biochemical free recurrence in prostate cancer
Clinical Cancer Research, 2003Co-Authors: Gustavo Ayala, Jennifer A Tuxhorn, Thomas M Wheeler, Anna Frolov, Peter T Scardino, Makoto Ohori, Marcus Wheeler, Jeffrey Spitler, David R RowleyAbstract:Extensive scientific literature data point to reciprocal interactions between prostate Stromal cells and prostate cancer cells that likely regulate tumor progression. To investigate whether these intratumoral-reactive Stromal cells in human prostate cancer are predictive of survival, tumor Stroma volume and specific Stroma markers were quantitated by using tissue microarrays (index tumors of 847 patients), and the results were analyzed relative to the recurrence-free survival data set for these patients. Tumor tissue was evaluated with Masson’s trichrome stains and by immunohistochemistry with antibody probes to smooth muscle α-actin, desmin, vimentin, pro-collagen type I, and calponin. The relative volume of intratumor Stroma (5% Stroma, grade 0; 5–15%, grade 1; 15–50%, grade 2; >50%, grade 3) and the expression index of Stromal marker (staining intensity grade × percentage of positive cells per field) were quantitated and analyzed. Interpretable data were obtained from 545 patients. Statistical analysis of the survival data set showed that the volume of reactive Stroma in the tumor was a significant predictor of disease-free survival. Stroma volume was most optimal as an independent predictor in tumors containing Stroma, defined as Gleason 7 and lower grades. Of interest, tumors with either little to no Stroma or tumors with abundant Stroma each showed reduced recurrence-free survival. For specific Stromal markers, reduced desmin and smooth muscle α-actin were hallmarks of cancer-associated reactive Stroma relative to normal fibromuscular Stroma. Quantitative analysis of desmin and smooth muscle α-actin expression showed both to be significant and independent predictors of recurrence-free survival. This is the first study to demonstrate that nonepithelial-reactive Stroma elements in prostate cancer tumors can be used as prognostic indicators. These data also add to the concept that tumors are not purely epithelial and the tumor-reactive Stroma must be considered an important biological component of the cancer.
-
reactive Stroma in human prostate cancer induction of myofibroblast phenotype and extracellular matrix remodeling
Clinical Cancer Research, 2002Co-Authors: Jennifer A Tuxhorn, Gustavo Ayala, Megan J Smith, Vincent C Smith, Truong D Dang, David R RowleyAbstract:Purpose: Generation of a reactive Stroma environment occurs in many human cancers and is likely to promote tumorigenesis. However, reactive Stroma in human prostate cancer has not been defined. We examined Stromal cell phenotype and expression of extracellular matrix components in an effort to define the reactive Stroma environment and to determine its ontogeny during prostate cancer progression. Experimental Design: Normal prostate, prostatic intraepithelial neoplasia (PIN), and prostate cancer were examined by immunohistochemistry. Tissue samples included radical prostatectomy specimens, frozen biopsy specimens, and a prostate cancer tissue microarray. A human prostate Stromal cell line was used to determine whether transforming growth factor β1 (TGF-β1) regulates reactive Stroma. Results: Compared with normal prostate tissue, reactive Stroma in Gleason 3 prostate cancer showed increased vimentin staining and decreased calponin staining ( P In vitro , TGF-β1 stimulated human prostatic fibroblasts to switch to the myofibroblast phenotype and to express tenascin. Conclusions: The Stromal microenvironment in human prostate cancer is altered compared with normal Stroma and exhibits features of a wound repair Stroma. Reactive Stroma is composed of myofibroblasts and fibroblasts stimulated to express extracellular matrix components. Reactive Stroma appears to be initiated during PIN and evolve with cancer progression to effectively displace the normal fibromuscular Stroma. These studies and others suggest that TGF-β1 is a candidate regulator of reactive Stroma during prostate cancer progression.
-
reactive Stroma in prostate cancer progression
The Journal of Urology, 2001Co-Authors: Jennifer A Tuxhorn, Gustavo Ayala, David R RowleyAbstract:Purpose: The development of an altered Stromal microenvironment in response to carcinoma is a common feature of many tumors. We reviewed the literature describing characteristics of reactive Stroma, how reactive Stroma affects cancer progression and how carcinoma regulates reactive Stroma. Moreover, we present a hypothesis of reactive Stroma in prostate cancer and discuss how the biology of reactive Stroma may be used in novel diagnostic and therapeutic approaches.Materials and Methods: An extensive literature search was performed to review reports of the general features of wound repair Stroma, general Stromal responses to carcinoma, and Stromal biology of normal and prostate cancer tissues. These studies were analyzed and a reactive Stroma hypothesis in prostate cancer was developed.Results: Modifications to the Stroma of breast, colon and prostate tumors parallel the generation of granulation tissue in wound repair. These changes include Stromal cell phenotypic switching, extracellular matrix remodelin...
Federica Sotgia - One of the best experts on this subject based on the ideXlab platform.
-
Understanding the Warburg effect and the prognostic value of Stromal caveolin-1 as a marker of a lethal tumor microenvironment
Breast Cancer Research, 2011Co-Authors: Federica Sotgia, Ubaldo E. Martinez-outschoorn, Stephanos Pavlides, Anthony Howell, Richard G Pestell, Michael P. LisantiAbstract:Cancer cells show a broad spectrum of bioenergetic states, with some cells using aerobic glycolysis while others rely on oxidative phosphorylation as their main source of energy. In addition, there is mounting evidence that metabolic coupling occurs in aggressive tumors, between epithelial cancer cells and the Stromal compartment, and between well-oxygenated and hypoxic compartments. We recently showed that oxidative stress in the tumor Stroma, due to aerobic glycolysis and mitochondrial dysfunction, is important for cancer cell mutagenesis and tumor progression. More specifically , increased autophagy/mitophagy in the tumor Stroma drives a form of parasitic epithelial-Stromal metabolic coupling. These findings explain why it is effective to treat tumors with either inducers or inhibitors of autophagy, as both would disrupt this energetic coupling. We also discuss evidence that glutamine addiction in cancer cells produces ammonia via oxidative mitochondrial metabolism. Ammonia production in cancer cells, in turn, could then help maintain autophagy in the tumor Stromal compartment. In this vicious cycle, the initial glutamine provided to cancer cells would be produced by autophagy in the tumor Stroma. Thus, we believe that parasitic epithelial-Stromal metabolic coupling has important implications for cancer diagnosis and therapy, for example, in designing novel metabolic imaging techniques and establishing new targeted therapies. In direct support of this notion, we identified a loss of Stromal caveolin-1 as a marker of oxidative stress, hypoxia, and autophagy in the tumor microenvironment, explaining its powerful predictive value. Loss of Stromal caveolin-1 in breast cancers is associated with early tumor recurrence, metastasis, and drug resistance, leading to poor clinical outcome.
-
Accelerated aging in the tumor microenvironment: Connecting aging, inflammation and cancer metabolism with personalized medicine
Cell Cycle, 2011Co-Authors: Michael P. Lisanti, Diana Whitaker-menezes, Ubaldo E. Martinez-outschoorn, Stephanos Pavlides, Anthony Howell, Richard G Pestell, Federica SotgiaAbstract:Cancer is thought to be a disease associated with aging. Interestingly, normal aging is driven by the production of ROS and mitochondrial oxidative stress, resulting in the cumulative accumulation of DNA damage. Here, we discuss how ROS signaling, NFκB- and HIF1-activation in the tumor microenvironment induces a form of "accelerated aging," which leads to Stromal inflammation and changes in cancer cell metabolism. Thus, we present a unified model where aging (ROS), inflammation (NFκB) and cancer metabolism (HIF1), act as co-conspirators to drive autophagy ("self-eating") in the tumor Stroma. Then, autophagy in the tumor Stroma provides high-energy "fuel" and the necessary chemical building blocks, for accelerated tumor growth and metastasis. Stromal ROS production acts as a "mutagenic motor" and allows cancer cells to buffer-at a distance-exactly how much of a mutagenic stimulus they receive, further driving tumor cell selection and evolution. Surviving cancer cells would be selected for the ability to induce ROS more effectively in Stromal fibroblasts, so they could extract more nutrients from the Stroma via autophagy. If lethal cancer is a disease of "accelerated host aging" in the tumor Stroma, then cancer patients may benefit from therapy with powerful antioxidants. Antioxidant therapy should block the resulting DNA damage, and halt autophagy in the tumor Stroma, effectively "cutting off the fuel supply" for cancer cells. These findings have important new implications for personalized cancer medicine, as they link aging, inflammation and cancer metabolism with novel strategies for more effective cancer diagnostics and therapeutics.
-
understanding the lethal drivers of tumor Stroma co evolution emerging role s for hypoxia oxidative stress and autophagy mitophagy in the tumor micro environment
Cancer Biology & Therapy, 2010Co-Authors: Michael P. Lisanti, Stephanos Pavlides, Anthony Howell, Ubaldo E Martinezoutschoorn, Barbara Chiavarina, Diana Whitakermenezes, Aristotelis Tsirigos, Agnieszka K Witkiewicz, Renee M Balliet, Federica SotgiaAbstract:We have recently proposed a new model for understanding how tumors evolve. To achieve successful "Tumor-Stroma Co-Evolution", cancer cells induce oxidative stress in adjacent fibroblasts and possibly other Stromal cells. Oxidative stress in the tumor Stroma mimics the effects of hypoxia, under aerobic conditions, resulting in an excess production of reactive oxygen species (ROS). Excess Stromal production of ROS drives the onset of an anti-oxidant defense in adjacent cancer cells, protecting them from apoptosis. Moreover, excess Stromal ROS production has a "Bystander-Effect", leading to DNA damage and aneuploidy in adjacent cancer cells, both hallmarks of genomic instability. Finally, ROS-driven oxidative stress induces autophagy and mitophagy in the tumor micro-environment, leading to the Stromal over-production of recycled nutrients (including energy-rich metabolites, such as ketones and L-lactate). These recycled nutrients or chemical building blocks then help drive mitochondrial biogenesis in cancer ...
Michael P. Lisanti - One of the best experts on this subject based on the ideXlab platform.
-
Understanding the Warburg effect and the prognostic value of Stromal caveolin-1 as a marker of a lethal tumor microenvironment
Breast Cancer Research, 2011Co-Authors: Federica Sotgia, Ubaldo E. Martinez-outschoorn, Stephanos Pavlides, Anthony Howell, Richard G Pestell, Michael P. LisantiAbstract:Cancer cells show a broad spectrum of bioenergetic states, with some cells using aerobic glycolysis while others rely on oxidative phosphorylation as their main source of energy. In addition, there is mounting evidence that metabolic coupling occurs in aggressive tumors, between epithelial cancer cells and the Stromal compartment, and between well-oxygenated and hypoxic compartments. We recently showed that oxidative stress in the tumor Stroma, due to aerobic glycolysis and mitochondrial dysfunction, is important for cancer cell mutagenesis and tumor progression. More specifically , increased autophagy/mitophagy in the tumor Stroma drives a form of parasitic epithelial-Stromal metabolic coupling. These findings explain why it is effective to treat tumors with either inducers or inhibitors of autophagy, as both would disrupt this energetic coupling. We also discuss evidence that glutamine addiction in cancer cells produces ammonia via oxidative mitochondrial metabolism. Ammonia production in cancer cells, in turn, could then help maintain autophagy in the tumor Stromal compartment. In this vicious cycle, the initial glutamine provided to cancer cells would be produced by autophagy in the tumor Stroma. Thus, we believe that parasitic epithelial-Stromal metabolic coupling has important implications for cancer diagnosis and therapy, for example, in designing novel metabolic imaging techniques and establishing new targeted therapies. In direct support of this notion, we identified a loss of Stromal caveolin-1 as a marker of oxidative stress, hypoxia, and autophagy in the tumor microenvironment, explaining its powerful predictive value. Loss of Stromal caveolin-1 in breast cancers is associated with early tumor recurrence, metastasis, and drug resistance, leading to poor clinical outcome.
-
Accelerated aging in the tumor microenvironment: Connecting aging, inflammation and cancer metabolism with personalized medicine
Cell Cycle, 2011Co-Authors: Michael P. Lisanti, Diana Whitaker-menezes, Ubaldo E. Martinez-outschoorn, Stephanos Pavlides, Anthony Howell, Richard G Pestell, Federica SotgiaAbstract:Cancer is thought to be a disease associated with aging. Interestingly, normal aging is driven by the production of ROS and mitochondrial oxidative stress, resulting in the cumulative accumulation of DNA damage. Here, we discuss how ROS signaling, NFκB- and HIF1-activation in the tumor microenvironment induces a form of "accelerated aging," which leads to Stromal inflammation and changes in cancer cell metabolism. Thus, we present a unified model where aging (ROS), inflammation (NFκB) and cancer metabolism (HIF1), act as co-conspirators to drive autophagy ("self-eating") in the tumor Stroma. Then, autophagy in the tumor Stroma provides high-energy "fuel" and the necessary chemical building blocks, for accelerated tumor growth and metastasis. Stromal ROS production acts as a "mutagenic motor" and allows cancer cells to buffer-at a distance-exactly how much of a mutagenic stimulus they receive, further driving tumor cell selection and evolution. Surviving cancer cells would be selected for the ability to induce ROS more effectively in Stromal fibroblasts, so they could extract more nutrients from the Stroma via autophagy. If lethal cancer is a disease of "accelerated host aging" in the tumor Stroma, then cancer patients may benefit from therapy with powerful antioxidants. Antioxidant therapy should block the resulting DNA damage, and halt autophagy in the tumor Stroma, effectively "cutting off the fuel supply" for cancer cells. These findings have important new implications for personalized cancer medicine, as they link aging, inflammation and cancer metabolism with novel strategies for more effective cancer diagnostics and therapeutics.
-
understanding the lethal drivers of tumor Stroma co evolution emerging role s for hypoxia oxidative stress and autophagy mitophagy in the tumor micro environment
Cancer Biology & Therapy, 2010Co-Authors: Michael P. Lisanti, Stephanos Pavlides, Anthony Howell, Ubaldo E Martinezoutschoorn, Barbara Chiavarina, Diana Whitakermenezes, Aristotelis Tsirigos, Agnieszka K Witkiewicz, Renee M Balliet, Federica SotgiaAbstract:We have recently proposed a new model for understanding how tumors evolve. To achieve successful "Tumor-Stroma Co-Evolution", cancer cells induce oxidative stress in adjacent fibroblasts and possibly other Stromal cells. Oxidative stress in the tumor Stroma mimics the effects of hypoxia, under aerobic conditions, resulting in an excess production of reactive oxygen species (ROS). Excess Stromal production of ROS drives the onset of an anti-oxidant defense in adjacent cancer cells, protecting them from apoptosis. Moreover, excess Stromal ROS production has a "Bystander-Effect", leading to DNA damage and aneuploidy in adjacent cancer cells, both hallmarks of genomic instability. Finally, ROS-driven oxidative stress induces autophagy and mitophagy in the tumor micro-environment, leading to the Stromal over-production of recycled nutrients (including energy-rich metabolites, such as ketones and L-lactate). These recycled nutrients or chemical building blocks then help drive mitochondrial biogenesis in cancer ...
Jennifer A Tuxhorn - One of the best experts on this subject based on the ideXlab platform.
-
Reactive Stroma and tumor evolution
Cancer Research, 2005Co-Authors: David R Rowley, Jennifer A Tuxhorn, Feng Yang, Steven J. Ressler, Stephanie J. Mcalhany, Doug Strand, Isaiah G. Schauer, Dang D. DangAbstract:SY12-2 Our previous studies have shown that reactive Stroma in prostate cancer is characterized by progressive changes in Stromal cell phenotype from differentiated smooth muscle to an activated myofibroblast / fibroblast population. Reactive Stromal cells also exhibit elevated synthesis of pro-collagen I, tenascin, and fibroblast activation protein (FAP). In addition, we have shown that reactive Stroma originates immediately adjacent to premalignant prostatic intraepithelial neoplasia (PIN) foci in human prostate cancer. Many PIN foci also overexpress TGF-β1 suggesting this factor is a mediator of reactive Stroma. In addition to stimulating Stromal cell wound repair responses, TGF-β1 functions to stimulate angiogenesis by regulating endothelial-pericyte interactions, differentiation of pericytes, and vessel stability. Moreover, TGF-β1 regulates expression of Stromal growth factors important to wound repair Stroma and angiogenesis, including connective tissue growth factor (CTGF) and fibroblast growth factor-2 (FGF-2). Reactive Stroma in human PIN and cancer is associated with both elevated microvessel density and FGF-2 expression. Together, these data suggest that TGF-β1 and downstream regulators are critical for reactive Stroma biology and angiogenesis in the premalignant PIN cancer microenvironment. A central hypothesis is that epithelial overexpression of TGF-β1 in PIN induces a typical Stromal wound repair response via both direct and indirect actions mediated through downstream factors such as FGF-2. This Stromal response continues to co-evolve with the foci of epithelial carcinoma cells during cancer progression. It is likely that the co-evolution of a proper reactive Stroma is required for organ-confined progression of the carcinoma. Accordingly, it is becoming clearer that the reactive Stroma microenvironment is an important component of overall tumorigenesis and is likely to involve a complex interplay and feedback loops between key Stromal growth factors. We have developed the differential reactive Stroma (DRS) xenograft model to address the role of reactive Stroma, TGF-β1, CTGF and FGF-2 in prostate cancer. Differential tumorigenesis and angiogenesis was observed using different human prostate Stromal cell lines co-inoculated with LNCaP human prostate cancer cells into nude mice. The inclusion of either human or mouse prostate Stromal cells with LNCaP cancer cells resulted in a rapid and consistent angiogenesis and tumorigenesis as compared to LNCaP xenografts without the inclusion of Stromal cells. Inoculated Stromal cells were localized in reactive Stroma of resulting tumor and were also observed in the vessel wall in a perictye position, suggesting a direct role in angiogenesis. Gene expression analysis showed several TGF-β1 regulated genes (including CTGF) were differentially expressed in human prostate Stromal cells capable of supporting and promoting LNCaP xenograft tumors. Of interest, TGF-β1 was also shown to stimulate release of FGF-2 from prostate Stromal cells in vitro in a Smad3 dependent manner. Neutralization of TGF-β1 activity in xenograft LNCaP / Stromal cell tumors resulted in inhibited tumorigenesis and a significant (3.5 fold) reduction in microvessel density. Similarly, xenograft LNCaP tumors co-inoculated with TGF-β receptor II null or Smad3 dominant negative prostate Stromal cell lines resulted in significantly decreased tumorigenesis and angiogenesis. These data suggest that TGF-β1 is a key mediator of the immediate reactive Stroma microenvironment and functions directly and indirectly to stimulate epithelial tumorigenesis via actions in the Stromal compartment including the regulation of angiogenesis. To address the role of CTGF, FGF-2 and other TGF-β1 regulated genes, DRS tumors were constructed with Stromal cells engineered to overexpress genes of choice, either in a regulated manner (GeneSwitch) with Miphepristone (RU 486) or by transducing cells via retroviral infection. Prostate Stromal cells engineered to over express CTGF resulted in elevated tumorigenesis and a stimulation of angiogenesis during early LNCaP / Stromal cell xenograft tumor formation. Overexpression of FGF-2 in prostate Stromal cells resulted in an elevated Stromalization leading to fibrosis and differential tumor growth. Of interest, overexpression of FGF-2 in Stromal cells null for TGF-β receptor type II or positive for dominant negative Smad3, resulted in an overt Stromalization fibrosis that appeared to inhibit carcinoma cell survival in LNCaP / Stromal cell xenograft tumors. In addition, the overexpression or inclusion of recombinant ps20 (an additional TGF-β1 regulated gene) in Stromal cells resulted in increased tumorigenesis and angiogenesis. The ps20 protein also functioned to induce vascular cell adhesion molecule-1 (VCAM1) and induce the migration of human umbilical vein endothelial cells in vitro. These studies suggest that a principal function of carcinoma-expressed TGF-β1 in early prostate cancer is to induce a cascade of downstream regulatory factors in reactive Stroma, including CTGF, FGF-2, and ps20 which leads to a wound repair type of reactive Stroma response and induction of angiogenesis in the immediate tumor microenvironment. Our data suggests that the balanced actions of TGF-β1 and FGF-2 in the Stromal compartment may be what regulates the ratio of fibroblasts to myofibroblast cell types in carcinoma associated reactive Stroma. Moreover, it is appears that unbalanced action of FGF-2 in a Stromal environment that is restricted from TGF-β1 signaling, results in a non wound repair fibrosis type of Stromal response that might actually be tumor inhibitory. Together, these data suggest a complex feedback loop between TGF-β1 and FGF-2 signaling in tumor reactive Stroma and point to how significant the balanced Stromal response is to tumor progression. The reactive Stroma microenvironment might play a role in metastatic progression as well. A hallmark of more advanced prostate cancer progression is epithelial to mesenchymal transition (EMT) as evidenced by expression of mesenchymal markers and acquisition of a more migratory and invasive phenotype. These changes include a splice switch of the FGF receptor 2 IIIb to the IIIc isoform (FGFR2IIIc) and expression of FGF receptor 1 (FGFR1) in carcinoma cells. Both FGFR2IIIc and FGFR1 are cognate receptors for FGF-2. Carcinoma cells expressing these receptors would be expected to have a growth advantage in this reactive Stroma microenvironment, which is elevated in FGF-2 expression and possibly the release of FGF-2 protein. Accordingly, elevated FGF-2 in the adjacent reactive Stroma microenvironment might provide a selection advantage for carcinoma epithelial cells undergoing EMT and differential expression of these FGF receptors. This would be expected to lead to tumors that are composed of carcinoma cells expressing mesenchymal proteins with a more aggressive and invasive behavior. Together, these data suggest that reactive Stroma is important both in early progression of prostate cancer and during EMT changes, which ultimately lead to a Stromal-independent progression and metastasis. Our future studies will continue to be focused on dissecting key downstream signaling mechanisms and co-regulatory loops of TGF-β1, CTGF and FGF-2 action in reactive Stroma and carcinoma cell biology during prostate cancer progression.
-
reactive Stroma as a predictor of biochemical free recurrence in prostate cancer
Clinical Cancer Research, 2003Co-Authors: Gustavo Ayala, Jennifer A Tuxhorn, Thomas M Wheeler, Anna Frolov, Peter T Scardino, Makoto Ohori, Marcus Wheeler, Jeffrey Spitler, David R RowleyAbstract:Extensive scientific literature data point to reciprocal interactions between prostate Stromal cells and prostate cancer cells that likely regulate tumor progression. To investigate whether these intratumoral-reactive Stromal cells in human prostate cancer are predictive of survival, tumor Stroma volume and specific Stroma markers were quantitated by using tissue microarrays (index tumors of 847 patients), and the results were analyzed relative to the recurrence-free survival data set for these patients. Tumor tissue was evaluated with Masson’s trichrome stains and by immunohistochemistry with antibody probes to smooth muscle α-actin, desmin, vimentin, pro-collagen type I, and calponin. The relative volume of intratumor Stroma (5% Stroma, grade 0; 5–15%, grade 1; 15–50%, grade 2; >50%, grade 3) and the expression index of Stromal marker (staining intensity grade × percentage of positive cells per field) were quantitated and analyzed. Interpretable data were obtained from 545 patients. Statistical analysis of the survival data set showed that the volume of reactive Stroma in the tumor was a significant predictor of disease-free survival. Stroma volume was most optimal as an independent predictor in tumors containing Stroma, defined as Gleason 7 and lower grades. Of interest, tumors with either little to no Stroma or tumors with abundant Stroma each showed reduced recurrence-free survival. For specific Stromal markers, reduced desmin and smooth muscle α-actin were hallmarks of cancer-associated reactive Stroma relative to normal fibromuscular Stroma. Quantitative analysis of desmin and smooth muscle α-actin expression showed both to be significant and independent predictors of recurrence-free survival. This is the first study to demonstrate that nonepithelial-reactive Stroma elements in prostate cancer tumors can be used as prognostic indicators. These data also add to the concept that tumors are not purely epithelial and the tumor-reactive Stroma must be considered an important biological component of the cancer.
-
reactive Stroma in human prostate cancer induction of myofibroblast phenotype and extracellular matrix remodeling
Clinical Cancer Research, 2002Co-Authors: Jennifer A Tuxhorn, Gustavo Ayala, Megan J Smith, Vincent C Smith, Truong D Dang, David R RowleyAbstract:Purpose: Generation of a reactive Stroma environment occurs in many human cancers and is likely to promote tumorigenesis. However, reactive Stroma in human prostate cancer has not been defined. We examined Stromal cell phenotype and expression of extracellular matrix components in an effort to define the reactive Stroma environment and to determine its ontogeny during prostate cancer progression. Experimental Design: Normal prostate, prostatic intraepithelial neoplasia (PIN), and prostate cancer were examined by immunohistochemistry. Tissue samples included radical prostatectomy specimens, frozen biopsy specimens, and a prostate cancer tissue microarray. A human prostate Stromal cell line was used to determine whether transforming growth factor β1 (TGF-β1) regulates reactive Stroma. Results: Compared with normal prostate tissue, reactive Stroma in Gleason 3 prostate cancer showed increased vimentin staining and decreased calponin staining ( P In vitro , TGF-β1 stimulated human prostatic fibroblasts to switch to the myofibroblast phenotype and to express tenascin. Conclusions: The Stromal microenvironment in human prostate cancer is altered compared with normal Stroma and exhibits features of a wound repair Stroma. Reactive Stroma is composed of myofibroblasts and fibroblasts stimulated to express extracellular matrix components. Reactive Stroma appears to be initiated during PIN and evolve with cancer progression to effectively displace the normal fibromuscular Stroma. These studies and others suggest that TGF-β1 is a candidate regulator of reactive Stroma during prostate cancer progression.
-
reactive Stroma in prostate cancer progression
The Journal of Urology, 2001Co-Authors: Jennifer A Tuxhorn, Gustavo Ayala, David R RowleyAbstract:Purpose: The development of an altered Stromal microenvironment in response to carcinoma is a common feature of many tumors. We reviewed the literature describing characteristics of reactive Stroma, how reactive Stroma affects cancer progression and how carcinoma regulates reactive Stroma. Moreover, we present a hypothesis of reactive Stroma in prostate cancer and discuss how the biology of reactive Stroma may be used in novel diagnostic and therapeutic approaches.Materials and Methods: An extensive literature search was performed to review reports of the general features of wound repair Stroma, general Stromal responses to carcinoma, and Stromal biology of normal and prostate cancer tissues. These studies were analyzed and a reactive Stroma hypothesis in prostate cancer was developed.Results: Modifications to the Stroma of breast, colon and prostate tumors parallel the generation of granulation tissue in wound repair. These changes include Stromal cell phenotypic switching, extracellular matrix remodelin...
