bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 515: Progesterone receptor inhibition of efficient type I interferon signaling in breast cancer
Authors: Walter Katherine Rose , Goodman Merit , Hagan Christy 
Published: August 2019

Abstract
A vast majority (65-70%) of breast cancers express the progesterone receptor (PR), a nuclear receptor that is activated in response to its ligand progesterone. Compelling clinical trial data have suggested that progestins have a role in breast cancer development, independent of the widely studied estrogen receptor. The mechanism by which this occurs, however, is vastly understudied.
Traditionally, PR exerts its effects following ligand activation by translocating to the nucleus and binding to DNA where it affects the transcription of a variety of genes involved in growth, survival, and proliferation. Our lab has identified a novel subset of genes that have altered expression following PR activation. Interferon Stimulated Genes (ISGs)–primarily activated in response to interferon signaling (viral response pathway) –are repressed when PR is activated by its ligand.
In attempting to elucidate a mechanism by which PR exerts this effect, we have investigated crosstalk of PR with canonical interferon signaling proteins and have found that PR interacts with these proteins and significantly reduces their ability to become activated. STAT1, a crucial protein involved in the interferon signaling cascade, is unable to efficiently be phosphorylated when PR is activated with ligand. ChIP experiments have also shown that PR inhibits the machinery necessary for ISG transcription from efficiently binding ISG promoters, possibly explaining the reduction in ISG expression observed following PR activation. Because of the importance of this particular signaling cascade in normal cell biology, multiple mechanisms most likely exist to fully inhibit interferon signaling and experiments are currently underway to identify other possibilities to better define PR’s functionality in this context.
Evasion of the immune system is considered a Hallmark of Cancer and our preliminary data suggest a potential mechanism by which breast cancer is able to accomplish this. Activation of type I interferon signaling is an early step in marking tumors for immune clearance. By repressing ISG protein expression, it is possible that these tumors are able to avoid detection by host immune cells leading to tumor establishment and subsequent progression. This novel role of PR and progestins offers insight that could aid in improving upon established estrogen only-based therapies for prevention and treatment of hormone dependent breast cancers.
Citation Format: Katherine Rose Walter, Merit Goodman, Christy Hagan. Progesterone receptor inhibition of efficient type I interferon signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 515.
Abstract 5158: Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival
Authors: Patton Mary C. , Zubair Haseeb , Khan Mohammad Aslam , Singh Seema , Singh Ajay P. 
Published: August 2019

Abstract
Pancreatic tumors are characterized by poor vasculature and fibrous stromal tissue networksthat create an extensive hypoxic tumor microenvironment. Extracellular vesicles (EVs) play important roles in pancreatic tumor pathobiology by supporting inter-cellular communications. They arebroadly classified into three subtypes: exosomes (Exo; 30-150 nm), microvesicles (MVs; 100 nm-1 µm) and apoptotic bodies (Abs; 1-5 µm), according to their cellular origin. Here, we studied the effect of hypoxic stress on the release kinetics and size distribution of EVs in pancreatic cancer cells. Further, we also investigated the role of different EV subtypes in adaptive survival of pancreatic cancer cells under hypoxia.Our data demonstrated that under hypoxic conditions, pancreatic cancer cells (MiaPaCa and AsPC1) shed greater amount of EVs with most noticeable changes recorded for the small size EVs. Moreover, all EVs (small, moderate, large) showed a shift towards reduced size depending upon the extent of hypoxia. When examined for subtype-specific markers, we observed mixed profiles. Thrombospondin (marker for Abs) and Arf6 (marker for MVs) were exclusively detected in large and moderate size fractions, respectively, under both normoxia and hypoxia. However, CD9 (marker for Exo) was detected in both small and moderate size EVs under hypoxia. Furthermore, in release kinetics studies we observed cyclic increases in accumulation of EV subtypes under hypoxic conditions. In addition, our data demonstrated that EVs from hypoxic cancer cells promoted survival of cancer cells under hypoxia,with small EVs being the most active. Altogether, our findings establish that hypoxia alters shedding of EVs in supporting adaptive survival of pancreatic cancer cells; associated differences could possibly be exploited for effective cancer management.
Citation Format: Mary C. Patton, Haseeb Zubair, Mohammad Aslam Khan, Seema Singh, Ajay P. Singh. Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5158.
Abstract 5160: Extracellular vesicles from scirrhous gastric cancer cells induce premetastatic niche formation for peritoneal metastasis
Authors: Okuno Tomohisa , Yashiro Masakazu , Kushiyama Shuhei , Nishimura Sadaaki , Togano Shingo , Kuroda Kenji , Tamura Tatsuro , Toyokawa Takahiro , Tanaka Hiroaki , Muguruma Kazuya , Hirakawa Kosei , Ohira Masaichi 
Published: August 2019

Abstract
Background: Human scirrhous gastric carcinoma (SGC) is also known as diffusely infiltrating carcinoma, type 4 on Borrmann’s criteria, and linitis plastica-type carcinoma. SGC is characterized by frequent peritoneal metastasis, high proliferation and infiltration activity with extensive fibrosis in the tumor stroma. We previously reported that a soluble factor(s) from SGC cells changed the peritoneum to pre-metastatic niche such as round shape of mesothelial cells and peritoneal fibrosis, which is a favorable environment for cancer cells to metastasize. Extracellular vesicles (EVs; Exosomes) might be one of soluble factor(s) which might change the peritoneal component to pre-metastatic niche. In this study, we investigated the effect of EVs from SGC cells on the pre-metastatic niche formation of the peritoneum.
Methods: Four SGC cell lines, OCUM-2M, OCUM-2MD3, OCUM-12, KATO-III, 2 non-SGC cell lines, MKN74, MKN45, and peritoneal mesothelial cells (PM cells) were used. The effect of EVs from gastric cancer cells on the peritoneum was examined in vitro and in vivo, as follows. PKH26-labeled EVs from OCUM-2MD3 cells were intravenously injected into nude mice for 3 weeks, then we examined the distribution of PKH26-labeled EVs by a fluorescence microscope. Next, we injected EVs intraperitoneally into nude mice, and investigated the morphology of peritoneum. Effect of EVs on the gene expression of PM cells was examined by RT-PCR. Clinical significance of EVs markers, CD9 and CD63, was evaluated by immunohistochemistry using 63 human gastric cancer specimens.
Results: PKH26-labeled EVs frequently distributed to peritoneum and the liver. The morphology of PM cells changed from round shape to spindle shape by EVs addiction in vitro and in vivo. mRNA expression level of ZEB and N-cadherin of PM cells was significantly increased following the addiction of EVs. The high expression of EVs
markers, CD9 and CD63, was significantly correlated with frequent peritoneal metastasis.
Conclusion: EVs from SGC cells might frequently distribute to mesothelial cells of peritoneum. EVs from SGC cells might play an important role for the formation of a pre-metastatic niche on peritoneum by the morphologic change of peritoneal mesothelial cells.
Citation Format: Tomohisa Okuno, Masakazu Yashiro, Shuhei Kushiyama, Sadaaki Nishimura, Shingo Togano, Kenji Kuroda, Tatsuro Tamura, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira. Extracellular vesicles from scirrhous gastric cancer cells induce premetastatic niche formation for peritoneal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5160.
Abstract 5163: Angiocrine induction of colorectal cancer cell HER3 activation and cell survival is independent of CRC mutational status
Authors: Wang Rui , Bhattacharya Rajat , Fan Fan , Ye Xiangcang , Ellis Lee M. 
Published: August 2019

Abstract
INTRODUCTION: Colorectal cancer (CRC) is the second-leading cause of cancer-related death in the United States. A better understanding of the regulation of CRC cell survival pathways is necessary for developing new therapeutic strategies for patients with metastatic CRC (mCRC). We have previously found that endothelial cells (ECs) from the liver, the most common site of CRC metastases, secrete soluble factors in their conditioned medium (CM) that, in turn, increase cell growth and chemoresistance of CRC cells. We also determined that EC-induced CRC cell survival is mediated, in part, by HER3/ERRB3 signaling.
OBJECTIVES: In the current study we sought to determine if alterations in driver mutations mediate the role of liver ECs in activating HER3 signaling and promoting cell survival in CRC cells.
METHODS: Primary ECs from non-malignant liver parenchyma were isolated as previously described (Wang et al., Mol Cancer Res., 2018). CRC cell lines with distinct molecular profiles (MSI status, and wildtype or mutant KRAS, BRAF, and PIK3CA) were incubated with either their own CM (control) or CM from ECs. The effects of CM on CRC cell growth and response to 5-fluorouracil (5-FU) was determined by MTT and colony formation assays. The effect of angiocrine signaling on chemoresistance was also determined by fluorescence-activated cell sorting (FACS) for apoptosis after treating CRC cells with 5-FU, either in control CM or EC CM. HER3 blockade was accomplished by 1) siRNA knockdown or 2) a HER3 antibody.
RESULTS: CM from liver ECs significantly increased cell growth and chemoresistance in CRC cells regardless of the gene alteration profiles in in vitro assays. We confirmed that EC CM activated the HER3-AKT signaling pathway in CRC cells. Furthermore, we found that HER3 blockade attenuated EC CM-induced AKT activation and cell survival in CRC cells independent of the cell mutational profile.
CONCLUSIONS: Our results demonstrate that HER3 mediates liver EC-induced cell growth and chemoresistance in CRC cells independent of the driver mutational profiles of the cells. The genetic background of CRC cells is not a mediator of EC CM-induced HER3 activation and cell survival. These findings suggest that effects of HER3 targeting of tumor cells in patients with mCRC should be independent of MSI status, or RAS, BRAF, or PIK3CA mutational status.
Citation Format: Rui Wang, Rajat Bhattacharya, Fan Fan, Xiangcang Ye, Lee M. Ellis. Angiocrine induction of colorectal cancer cell HER3 activation and cell survival is independent of CRC mutational status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5163.
Abstract 5164: Signaling crosstalk within prostate tumor microenvironment mediates castrate resistant disease progression
Authors: Tripathi Manisha , Nandana Srinivas , Huang Jen-Ming , Kato Manabu , Mishra Rajeev , Chung Leland , Xin Li , Bhowmick Neil 
Published: August 2019

Abstract
Juxtacrine signaling with the stromal compartment is important to the development of castrate resistance prostate cancer. We found that Notch signaling is upregulated in prostate cancer associated fibroblasts (CAFs) compared with normal tissue associated fibroblasts (NAFs). Further, inhibition of Notch signaling in CAFs resulted in decreased Wnt signaling and decrease in expression of Notch pathway genes. Interestingly, androgen receptor antagonism resulted in increased Notch signaling and the upregulation of downstream Wnts. Further, generation of chimeric tissue recombinant xenografts with human RV1 prostate cancer epithelia with mouse prostate stromal cells with activated Notch signaling that are derived from NICD transgenic mice resulted in increased tumor size compared with wild type control stromal recombinants. Conversely, recombinants derived from prostatic fibroblasts of RBPJ-knockout mice that have a loss of Notch signaling demonstrated diminished tumorigenesis, compared with xenografts with the wild type fibroblasts. In trying to determine the mediator of Wnt-associated paracrine prostate epithelial expansion, we found downstream YAP activation in the RV1 cells. In a reciprocal epithelial-to-fibroblast communication we found that the RV1 cells treated with conditioned media from NICD fibroblasts showed increased IL-6 expression. Conversely, conditioned media from prostate cancer cells caused increased Notch target gene expression in CAFs, which was blocked upon addition of IL-6 neutralizing antibody. Taken together our results suggest that there is a stromal-derived feed-back - feed-forward signaling loop involving Notch and Wnt ligands that activates YAP in the epithelia for paracrine IL-6-dependent Notch activity back in the stromal fibroblasts. Critically, disruption of this cross-talk in the fibroblasts can potentially limit the gain of stem features and castrate resistance of the adjacent epithelia in halting lethal progression of prostate cancer.
Citation Format: Manisha Tripathi, Srinivas Nandana, Jen-Ming Huang, Manabu Kato, Rajeev Mishra, Leland Chung, Li Xin, Neil Bhowmick. Signaling crosstalk within prostate tumor microenvironment mediates castrate resistant disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5164.
Abstract 517: Supraphysiological androgens activate innate immune signaling in prostate cancer
Authors: Mendonca Janet , Owoyemi Olutosin , Rosen Marc , Carducci Michael , Markowski Mark , Antonarakis Emmanuel , Pardoll Drew , Denmeade Samuel , Kachhap Sushant K. 
Published: August 2019

Abstract
Castration resistance prostate cancer (CRPC) first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of a functioning androgen receptor (AR) axis. This observation led to the development of “second-line” therapies aimed at further blocking androgen/AR signaling. Unfortunately, resistance to these agents can also develop quickly. Paradoxically, several studies have suggested that the growth of AR-positive human CRPC cell lines may be inhibited by supraphysiologic levels of testosterone (SupT). These studies suggested that the adaptive reliance on AR signaling by CRPC cells becomes a therapeutic liability that can be exploited through the administration of SupT, which we termed as bipolar androgen therapy (BAT). Understanding how BAT works at the molecular and cellular levels might help in rationally combining BAT with other agents to achieve increased efficacy and tumor responses. Our data indicates that SupT induces DNA double strand breaks (DSBs) in prostate cancer (PCa) cells. Unrepaired DSBs induced by SupT are routed for specialized autophagic degradation, termed nucleophagy. We further show that SupT-induced autophagosomal DNA can activate cytoplasmic DNA sensing pathways and downstream innate immune signaling. Based on our findings, we propose that BAT engages the immune system to inhibit tumor growth. Future combination of BAT with existing immunotherapeutics including immune checkpoint blockade may prove beneficial for treatment of CRPC.
Citation Format: Janet Mendonca, Olutosin Owoyemi, Marc Rosen, Michael Carducci, Mark Markowski, Emmanuel Antonarakis, Drew Pardoll, Samuel Denmeade, Sushant K. Kachhap. Supraphysiological androgens activate innate immune signaling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 517.
Abstract 5170: Targeting FGFR signaling to disrupt cellular cross-talk in pancreatic cancer
Authors: Coetzee Abigail , Carter Edward , Heward James , Mardakheh Faraz , Grose Richard , Kocher Hemant 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5 year survival rate of less than 5%. PDAC tumors consist of a desmoplastic stroma, which limits the effectiveness of chemotherapy. Pancreatic stellate cells (PSCs), which form a key part of this stroma, become activated in response to tumor development. Activated PSCs enter a cross-talk with cancer cells to induce tumor cell proliferation and invasion, leading to metastatic spread. Nuclear fibroblast growth factor receptor 1 (nFGFR1) has been found in PSCs at the invasive edge of PDAC tumors. Inhibition of FGFR1 prevents its nuclear translocation in PSCs, which results in decreased invasion in 3D in vitro PDAC models. Nuclear translocation of FGFR1 in PSCs appears to be a vital mechanism that triggers the transcription of key proteins involved in PDAC invasion.
We have used a powerful combination of chromatin immunoprecipitation (ChIP-seq) and sub-cellular mass spectrometry to determine the transcriptional targets of nFGFR1 and consequent sub-cellular protein flux. These techniques have allowed us to dissect the functional consequences of FGFR1 knockdown or inhibition in the PSCs. Candidate drivers of invasion are being validated in state-of-the-art 3D in vitro PDAC models. We have extended these functional studies to combination therapy with the clinical agent gemcitabine (targeting cancer cells) and all-trans retinoic acid (ATRA, modulating PSCs), providing translational relevance for our findings. We are embarking on validating this novel strategy using in vivo co-culture xenograft models with specific reference to FGFR1. Effectively disrupting the cross-talk between the tumor and stroma, either alone or in combination with other therapies, could translate to improved therapeutic responses in PDAC patients in the clinic.
Citation Format: Abigail Coetzee, Edward Carter, James Heward, Faraz Mardakheh, Richard Grose, Hemant Kocher. Targeting FGFR signaling to disrupt cellular cross-talk in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5170.
Abstract 5171: GRP78 as a potential modulator of cell adhesion markers in metastatic prostate cancer and multiple myeloma
Authors: Cultrara Christopher , Sabatino David , Zilberberg Jenny 
Published: August 2019

Abstract
Background: Glucose regulated protein 78 (GRP78) is a resident chaperone of the endoplasmic reticulum and a master regulator of the unfolded protein response under physiological and pathological cell stress conditions. GRP78 is overexpressed in many cancers, regulating a variety of signaling pathways associated with tumor initiation, proliferation, adhesion and invasion which contributes to metastatic spread. GRP78 can also regulate cell survival and apoptotic pathways to alter responsiveness to anticancer drugs. Tumors that reside in or metastasize to the bone and bone marrow (BM) space can develop pro-survival signals through their direct adhesive interactions with stromal elements of this niche thereby resisting the cytotoxic effects of drug treatment. In this study, we report a direct correlation between GRP78 and the adhesion molecule N-cadherin (N-cad), known to play a critical role in the adhesive interactions of multiple myeloma and metastatic prostate cancer with the bone microenvironment.
Methods: N-cad expression levels (transcription and protein) were evaluated upon siRNA mediated silencing of GRP78 in the MM.1S multiple myeloma and the PC3 metastatic prostate cancer cell lines. Furthermore, we evaluated the effects of GRP78 knockdown (KD) on epithelial-mesenchymal (EMT) transition markers, morphological changes and adhesion of PC3 cells.
Results: We demonstrate that GRP78 KD: 1) induced the concomitant downregulation of N-cad in both PC3 and MM.1S cells, 2) resulted in significant decreases of both N-cad and E-cad protein levels in PC3 cells, 3) induced TGF-β1 and Snail-2 expression, potentially accounting for the observed downregulation of E-cad. Our data also suggests that N-cad regulation via GRP78 KD supersedes the effects of TGF-β1; i.e., N-cad was downregulated in spite of the fact that TGF-β1 expression was significantly increased upon GRP78 KD.
Conclusion: This work implicates GRP78 as a modulator of cell adhesion markers in MM and PCa. Our results may have clinical implications underscoring GRP78 as a potential therapeutic target to reduce the adhesive nature of metastatic tumors to the bone niche.
Citation Format: Christopher Cultrara, David Sabatino, Jenny Zilberberg. GRP78 as a potential modulator of cell adhesion markers in metastatic prostate cancer and multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5171.
Abstract 5172: Deposition of platelets in sinusoids and its contribution to hepatocarcinogenesis
Authors: Tanaka Hiroki , Horioka Kie , Yamamoto Masahiro , Sawada Koji , Hasebe Takumu , Yamazaki Kosuke , Ogawa Katsuhiro 
Published: August 2019

Abstract
Platelets can activate hepatocyte proliferation not only via releasing the platelet factors, but also promoting for liver sinusoidal endothelial cells (LSEC) and Kupffer cells to produce the factors such as IL-6 and TGF-α that are indispensable for hepatocyte proliferation. We previously reported that in the transgenic (TG) mice with liver specific human BRAFV600E mutation, which corresponds to the mouse BrafV637E that is highly prevalent in mouse DEN-induced hepatic tumors, exhibit increased liver weight five times larger than that of normal mice. Furthermore, hepatocytes in these mice overexpress thrombopoietin (TPO) in association with megakaryocytosis/thrombocytosis, and large numbers of platelets were deposited in the liver sinusoids. In the present study, we investigated whether platelets are deposited in liver sinusoids in hepatic tumors in human and mice. CD61 immunohistochemical staining revealed the increased numbers of platelets were deposited in the sinusoids in foci, adenomas and hepatocellular carcinomas (HCC) induced by neonatal treatment with DEN compared to surrounding normal hepatic tissues. Moreover, increased numbers of platelets were deposited in sinusoids of dysplastic nodules and well-differentiated HCC compared to normal liver tissue and cirrhotic nodules in human. In addition, we evaluated the correlation between the tumor diameters and peripheral platelets numbers in the patients who were primarily diagnosed as HCC in our institute. The result indicated that the numbers of peripheral platelets are positively correlated with the tumor diameters. These results indicate that platelets contribute to development of HCC via interacting sinusoidal cells.
Citation Format: Hiroki Tanaka, Kie Horioka, Masahiro Yamamoto, Koji Sawada, Takumu Hasebe, Kosuke Yamazaki, Katsuhiro Ogawa. Deposition of platelets in sinusoids and its contribution to hepatocarcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5172.