Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects

Satb1 overexpression drives tumor-promoting activities in cancer-associated dendritic cells

Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46(+) inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.Fil: Tesone, Amelia J.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Rutkowski, Melanie R.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Brencicova, Eva. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Svoronos, Nikolaos. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Perales Puchal, Alfredo. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Stephen, Tom L.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Allegrezza, Michael J.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Payne, Kyle K.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Nguyen, Jenny M.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Wickramasinghe, Jayamanna. The Wistar Institute. Center for Systems and Computational Biology; Estados UnidosFil: Tchou, Julia. University of Pennsylvania; Estados UnidosFil: Borowsky, Mark E.. Christiana Care Health System. Helen F. Graham Cancer Center; Estados UnidosFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Kossenkov, Andrew V.. The Wistar Institute. Center for Systems and Computational Biology; Estados UnidosFil: Conejo Garcia, José R.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unido

A Multi-Disciplinary Approach to Cancer Care: The Beginning of a New Era

No abstract available

Role of HOX Genes in Stem Cell Differentiation and Cancer.

HOX genes encode an evolutionarily conserved set of transcription factors that control how the phenotype of an organism becomes organized during development based on its genetic makeup. For example, in bilaterian-type animals, HOX genes are organized in gene clusters that encode anatomic segment identity, that is, whether the embryo will form with bilateral symmetry with a head (anterior), tail (posterior), back (dorsal), and belly (ventral). Although HOX genes are known to regulate stem cell (SC) differentiation and HOX genes are dysregulated in cancer, the mechanisms by which dysregulation of HOX genes in SCs causes cancer development is not fully understood. Therefore, the purpose of this manuscript was (i) to review the role of HOX genes in SC differentiation, particularly in embryonic, adult tissue-specific, and induced pluripotent SC, and (ii) to investigate how dysregulated HOX genes in SCs are responsible for the development of colorectal cancer (CRC) and acute myeloid leukemia (AML). We analyzed HOX gene expression in CRC and AML using information from The Cancer Genome Atlas study. Finally, we reviewed the literature on HOX genes and related therapeutics that might help us understand ways to develop SC-specific therapies that target aberrant HOX gene expression that contributes to cancer development

The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDH+ colon cancer stem cells and increased differentiation of stem cells

Background: Tumorigenesis is driven by stem cell (SC) overpopulation. BecauseALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA)signaling, we studied RA signaling in normal and malignant colonic SCs.Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonicSCs dysregulation of RA signaling contributes to SC overpopulation and colorectalcancer (CRC) development.Methods: We analyzed normal and malignant colonic tissues and CRC cell linesto see if retinoid receptors (RXR &RAR) are exclusively expressed in ALDH+ SCs,and if RA signaling changes during CRC development. We determined whether RAsignaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation,and population size.Results: RXR &RAR were expressed in ALDH+ colonic SCs, but not in MCM2+proliferative cells. Western blotting/immunostaining of CRCs revealed that RAsignaling components become overexpressed in parallel with ALDH overexpression,which coincides with the known overpopulation of ALDH+ SCs that occurs during,and drives, CRC development. Treatment of SCs with all-trans retinoic acid (ATRA)decreased proliferation, sphere formation and ALDH+ SC population size, and induceddifferentiation along the neuroendocrine cell (NEC) lineage.Conclusions: Retinoid signaling, by regulating ALDH+ colonic CSCs, decreases SCproliferation, sphere formation, and population size, and increases SC differentiation toNECs. Dysregulation of RA signaling in colonic SCs likely contributes to overpopulationof ALDH+ SCs and CRC growth.Implications: That retinoid receptors RXR and RAR are selectively expressed inALDH+ SCs indicates RA signaling mainly occurs via ALDH+ SCs, which provides amechanism to selectively target CSCs. © 2018 Impact Journals LLC. All rights reserved

The Role of miRNAs, miRNA Clusters, and isomiRs in Development of Cancer Stem Cell Populations in Colorectal Cancer.

MicroRNAs (miRNAs or miRs) have a critical role in regulating stem cells (SCs) duringdevelopment and altered expression can cause developmental defects and/or disease. Indeed,aberrant miRNA expression leads to wide-spread transcriptional dysregulation which has beenlinked to many cancers. Mounting evidence also indicates a role for miRNAs in the developmentof the cancer SC (CSC) phenotype. Our goal herein is to provide a review of: (i) current researchon miRNAs and their targets in colorectal cancer (CRC), and (ii) miRNAs that are differentiallyexpressed in colon CSCs. MicroRNAs can work in clusters or alone when targeting different SC genesto influence CSC phenotype. Accordingly, we discuss the specific miRNA cluster classifications andisomiRs that are predicted to target theALDH1,CD166,BMI1,LRIG1, andLGR5SC genes.miR-23bandmiR-92Aare of particular interest because our previously reported studies on miRNA expressionin isolated normal versus malignant human colonic SCs showed thatmiR-23bandmiR-92aareregulators of theLGR5andLRIG1SC genes, respectively. We also identify additional miRNAs whoseexpression inversely correlated with mRNA levels of their target genes and associated with CRCpatient survival. Altogether, our deliberation on miRNAs, their clusters, and isomiRs in regulationof SC genes could provide insight into how dysregulation of miRNAs leads to the emergence ofdifferent CSC populations and SC overpopulation in CRC

Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules

ObjectivesA single randomized trial established lobectomy as the standard of care for the surgical treatment of early-stage non–small cell lung cancer. Recent advances in imaging/staging modalities and detection of smaller tumors have once again rekindled interest in sublobar resection for early-stage disease. The objective of this study was to compare lung cancer survival in patients with non–small cell lung cancer with a diameter of 30 mm or less with clinical stage 1 disease who underwent lobectomy or sublobar resection.MethodsWe identified 347 patients diagnosed with lung cancer who underwent lobectomy (n = 294) or sublobar resection (n = 53) for non–small cell lung cancer manifesting as a solid nodule in the International Early Lung Cancer Action Program from 1993 to 2011. Differences in the distribution of the presurgical covariates between sublobar resection and lobectomy were assessed using unadjusted P values determined by logistic regression analysis. Propensity scoring was performed using the same covariates. Differences in the distribution of the same covariates between sublobar resection and lobectomy were assessed using adjusted P values determined by logistic regression analysis with adjustment for the propensity scores. Lung cancer–specific survival was determined by the Kaplan–Meier method. Cox survival regression analysis was used to compare sublobar resection with lobectomy, adjusted for the propensity scores, surgical, and pathology findings, when adjusted and stratified by propensity quintiles.ResultsAmong 347 patients, 10-year Kaplan–Meier for 53 patients treated by sublobar resection compared with 294 patients treated by lobectomy was 85% (95% confidence interval, 80-91) versus 86% (confidence interval, 75-96) (P = .86). Cox survival analysis showed no significant difference between sublobar resection and lobectomy when adjusted for propensity scores or when using propensity quintiles (P = .62 and P = .79, respectively). For those with cancers 20 mm or less in diameter, the 10-year rates were 88% (95% confidence interval, 82-93) versus 84% (95% confidence interval, 73-96) (P = .45), and Cox survival analysis showed no significant difference between sublobar resection and lobectomy using either approach (P = .42 and P = .52, respectively).ConclusionsSublobar resection and lobectomy have equivalent survival for patients with clinical stage IA non–small cell lung cancer in the context of computed tomography screening for lung cancer

ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R–mediated apoptosis

Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis–induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs