bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B48: The effects of different types of hypoxia on tumor progression in breast cancer
Authors: Chen Anna , Sceneay Jaclyn , Gödde Nathan , Thompson Erik , Humbert Patrick , Möller Andreas 
Published: May 2019

Abstract
Hypoxia, the state of low oxygen conditions, occurs frequently in solid tumors and is a poor prognostic factor. The expression of Hif-1α,the main mediator of the hypoxic response pathway, and the subsequent up-regulation of its target genes have been implicated in tumor growth, invasion, angiogenesis, therapy resistance and metastasis. There are two forms of hypoxia present in a growing tumor: chronic hypoxia (caused by limitations in oxygen diffusion from abnormal tumor vasculature) and intermittent hypoxia (caused by the aberrant, repeated and temporary closing and re-opening of blood vessels, leading to fluctuations in oxygen supply). This study investigates the phenotypes endowed by different forms of hypoxia that mediate metastatic potential in a syngeneic mouse model of breast cancer.
By exposing murine breast cancer cells to 9 days of 20% O2 (normoxia), 1% O2 (chronic hypoxia) or alternating 24 hour cycles in 20% O2 and 1% O2 (intermittent hypoxia), we observe that intermittent hypoxia produces tumor cells with greater metastatic potential. These treatments produce no difference in primary tumor growth when orthotopically injected into the mammary fat pad of female C57Bl/6 mice. However, intermittent hypoxia-treated cells give rise to a greater number of and larger lung metastases when injected intravenously via the tail-vein of female C57Bl/6 mice. Intermittent hypoxia, but not chronic hypoxia, up-regulated the expression of genes that predict lung metastasis in breast cancer, endowed cells with an enhanced ability for anchorage-independent growth and produced greater clonal diversity. Furthermore, intermittent hypoxia also caused a switch to glycolysis in cells and induced a pro-tumorigenic, immunosuppressive secretory profile in vitro. Finally, intermittent hypoxia up-regulated the expression of mammary stem cell genes, increased expression of stem cell marker Sca-1 as well as CD14, and generated tumor-initiating cells at a higher frequency as evidenced by in vivo limiting dilution assays.
This work demonstrates that intermittent hypoxia enhances metastatic seeding and outgrowth by priming cells intrinsically to metastasize, while activating co-operating factors that act extrinsically to form a permissive, immunosuppressive microenvironment. By delineating the contributions of different forms of hypoxia to metastasis, critical molecular mediators can be identified in aid of the development of efficacious therapies that could inhibit, prevent or cure metastatic disease.
Citation Format: Anna Chen, Jaclyn Sceneay, Nathan Gödde, Erik Thompson, Patrick Humbert, Andreas Möller. The effects of different types of hypoxia on tumor progression in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B48.
Abstract B49: Epithelial-mesenchymal plasticity primes inherent resistance to targeted therapies
Authors: Brown Wells S. , Wendt Michael 
Published: May 2019

Abstract
The metastasis and acquisition of drug resistance in breast cancer cells has been linked to epithelial-mesenchymal transition (EMT). Directed therapies using kinase inhibitors and antibodies to target human epidermal growth factor receptor 2 (Her2) have served as a testament to the potential of molecular-targeted therapies in this breast cancer subtype. However, Her2-targeted therapies are plagued by the pitfalls of intrinsic and acquired resistance, particularly in the metastatic setting. To address these questions we conducted long-term treatments of Her2-transformed cells with TGF-β. This treatment regime resulted in a robust and plastic EMT phenotype as characterized by their CD44/CD24 profile. Following removal of stimuli, cells that had undergone TGF-β-induced EMT enter into a highly heterogeneous state, the importance of which is evidenced by their increased in vivo tumor growth metastatic capability. Importantly, the Lapatinib resistant cell population that arises following TGF-β-induced EMT can be readily eliminated via treatment with recently developed covalent inhibitors of fibroblast growth receptor (FGFR). Overall our data demonstrate that the EMT processes induced by physiologic cytokine stimulation are not only critical drivers of metastatic progression but they also are key events in producing secondary tumors that are poised to be inherently resistant to clinically used targeted molecular therapies.
Citation Format: Wells S. Brown, Michael Wendt. Epithelial-mesenchymal plasticity primes inherent resistance to targeted therapies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B49.
Abstract B54: Sustained exposure to TGFβ1 increases the stability of Snail and Slug via integrin β3-Akt-GSK3β signaling, facilitating tumor cell invasion
Authors: Bae Gab-Yong , Cha Hyuk-Jin 
Published: May 2019

Abstract
TGFβ is considered as a strong inducer of epithelial-mesenchymal transition (EMT) of tumor cells, promoting metastasis. Whereas acute TGFβ exposure induces growth arrest, chronic TGFβ exposure provokes invasive properties with resistance to TGFβ-induced growth arrest. However, the effect of chronic TGFβ exposure on acquired invasive characteristics of tumor cells is not fully determined.
We established a trans-differentiated (TD) A549 cell model by chronic exposure of TGFβ1, with clear EMT phenotypes including high invasiveness. Of interest, elevated invasiveness of TD cells after additional TGFβ1 treatment was achieved even in the significantly downregulated Smad2/3 dependent signaling compared to control cells. We demonstrated that Snail and Slug, the expression of which was highly correlated with poor prognosis of lung cancer patients, were clearly increased in TD cells upon TGFβ1 stimulation due to high protein stability. The increased stability of Snail and Slug in TD cells was attributed to elevated inhibitory phosphorylation of GSK3β, which was caused by higher Akt activity. We demonstrated that dramatically increased integrin β3 by prolong TGFβ1 exposure was responsible for high activity of Akt and subsequent high protein stability of Snail and Slug. Thereby, our data suggest that targeting of integrin β3-mediated signaling would be a potential therapeutic strategy to inhibit invasive properties of TGFβ-stimulated lung cancer.
Citation Format: Gab-Yong Bae, Hyuk-Jin Cha. Sustained exposure to TGFβ1 increases the stability of Snail and Slug via integrin β3-Akt-GSK3β signaling, facilitating tumor cell invasion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B54.
Abstract B65: Promotion of colorectal cancer invasion and metastasis through activation of Notch–Dab1–Abl–RhoGEF protein trio
Authors: Sonoshita Masahiro , Itatani Yoshiro , Kakizaki Fumihiko , Sakai Yoshiharu , Taketo. M. Mark 
Published: May 2019

Abstract
We have recently identified a metastasis suppressor gene for colorectal cancer:
AES/Aes that encodes an endogenous inhibitor of Notch signaling (1). When Aes is knocked out in the adenomatous epithelium of intestinal polyposis mice, their tumors become malignant, showing marked submucosal invasion and intravasation. Here, we show that one of the genes induced by NOTCH signaling in colorectal cancer is DAB1/Dab1. Genetic depletion of DAB1 suppresses cancer invasion and metastasis in the NOTCH signaling-activated mice. DAB1 is phosphorylated by ABL tyrosine kinase, which activates ABL reciprocally. Consistently, inhibition of ABL suppresses cancer invasion in mice. Furthermore, we show that one of the targets of ABL is the RAC/RHOGEF protein TRIO, and that phosphorylation at its Tyr residue 2681 (pY2681) causes RHO activation in colorectal cancer cells. Its unphosphorylatable mutation TRIO Y2681F reduces Rho-GEF activity and inhibits invasion of colorectal cancer cells. Importantly, Trio (pY2681) correlates with significantly poorer prognosis of patients with colorectal cancer after surgery (2). These results indicate that Trio(pY2681) is one of the downstream effectors of Notch signaling activation in colorectal cancer, and can be a prognostic marker, helping to determine the therapeutic modality of patients with colorectal cancer. More recent results will be discussed.
(1) Cancer Cell; 19: 125–137, 2011.
(2) Cancer Discov; 5:198–211, 2015.
Citation Format: Masahiro Sonoshita, Yoshiro Itatani, Fumihiko Kakizaki, Yoshiharu Sakai, M. Mark Taketo. Promotion of colorectal cancer invasion and metastasis through activation of Notch–Dab1–Abl–RhoGEF protein trio. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B65.
Abstract IA04: Cancer-associated systemic inflammation facilitates breast cancer metastasis
Authors: Coffelt Seth B. , Kersten Kelly , Wellenstein Max , Doornebal Chris W. , Salvagno Camilla , Vrijland Kim , Hau Cheei-Sing , Jonkers Jos , Visser Karin E. de 
Published: May 2019

Abstract
Over 90% of breast cancer deaths are due to complications as a consequence of metastasis formation. Despite its devastating effects, metastatic disease is still poorly understood. Accumulating evidence indicates that cells and mediators of the immune system influence metastasis formation. In our lab, we use preclinical mouse models for metastatic breast cancer to dissect the impact of the immune system on the different steps of the metastatic cascade. Neutrophils make up a significant proportion of the inflammatory infiltrate in many tumors and their systemic accumulation in cancer patients has been associated with metastasis formation. Also in our recently developed spontaneous breast cancer metastasis mouse model that accurately mimics each step of the metastatic cascade in humans, metastasis formation is accompanied by pronounced systemic accumulation of neutrophils. Antibody-mediated depletion of neutrophils did not affect primary breast cancer outgrowth, but profoundly decreased spontaneous metastasis formation in lungs and lymph nodes. Using biological and genetic approaches, we have uncovered a novel mammary tumor-induced systemic communication network between gamma delta T cells and neutrophils that is critical for breast cancer metastasis. Our data indicate that targeting this novel cancer cell-initiated systemic inflammatory cascade represents a viable strategy to inhibit metastatic disease.
Citation Format: Seth B. Coffelt, Kelly Kersten, Max Wellenstein, Chris W. Doornebal, Camilla Salvagno, Kim Vrijland, Cheei-Sing Hau, Jos Jonkers, Karin E. de Visser. Cancer-associated systemic inflammation facilitates breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA04.
Abstract IA15: Lymphangiogenesis and metastasis of postpartum breast cancer
Authors: Schedin Pepper J. , Borges Virginia F. 
Published: May 2019

Abstract
Young women diagnosed with breast cancer have a 2-3 fold increased risk of metastatic disease if they are diagnosed within ten years of a completed pregnancy. We find a postpartum diagnosis to be a poor prognostic indicator independent of tumor stage and biologic subtype, leading to the investigation of whether postpartum breast involution is a mediator of metastasis. We show that human postpartum breast cancers have increased peritumor lymphatic vessel density that correlates with increased frequency of lymph node metastases. In addition, we show that breast cancer cells exposed to the involuting mammary microenvironment acquire pro-lymphangiogenic properties that contribute to peritumor lymphatic expansion, invasion, and distant metastases. This pro-lymphatic phenotype appears to be due to tumor cells hijacking developmentally-regulated programs normally restricted to the actively involuting mammary gland. Specifically, we find upregulation of lymphangiogenesis with weaning in the normal mammary glands of rodents and humans. Further, in rodent models of postpartum breast cancer, COX-2 inhibition limited to the involution window decreases normal mammary gland lymphangiogenesis, mammary tumor associated lymphangiogenesis, tumor cell invasion into lymphatics, and metastasis. Finally, we find that COX-2 inhibition also targets fibroblast activation and collagen production during mammary gland involution, raising the possibility that COX-2 orchestrates a whole tissue response that is supportive of tumor cell escape in the involuting gland. In summary, we show that physiologic COX-2 dependent fibroblast activation, collagen deposition, and lymphangiogenesis are coordinated in the postpartum mammary gland and suggest that tumors evolving in this unique microenvironment acquire enhanced pro-lymphangiogenic and pro-metastatic activities. These data provide further impetus for considering the use of COX-2 inhibitors in the treatment of postpartum breast cancer, and suggest novel prevention strategies targeted to recently pregnant women as well.
Citation Format: Pepper J. Schedin, Virginia F. Borges. Lymphangiogenesis and metastasis of postpartum breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA15.
Abstract IA23: Hematogenous metastasis of ovarian cancer: Rethinking mode of spread
Authors: Sood Anil K. 
Published: May 2019

Abstract
Most patients with ovarian cancer present with widely metastatic disease. Although epithelial ovarian cancer was widely believed to metastasize via direct surface spread, the distribution of metastasis from the primary tumor is not completely random. Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. We have used parabiosis model systems that demonstrate preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis.
Citation Format: Anil K. Sood. Hematogenous metastasis of ovarian cancer: Rethinking mode of spread. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA23.
Abstract IA27: The patient biosphere: Tumors live in people
Authors: Pienta Kenneth James , Amend Sarah R. 
Published: May 2019

Abstract
Ecosystems are interactive systems involving communities of species and their abiotic environment. Tumors are ecosystems in which cancer cells act as invasive species interacting with native host cell species. As they grow, tumors fundamentally alter their microenvironment, disrupting the homeostasis of the host organ and eventually the patient as a whole. Lethality is the ultimate result of deregulated cell signaling and regulatory mechanisms as well as inappropriate host cell recruitment and activity that lead to the death of the patient. These processes have striking parallels to the framework of ecological biology: multiple interacting ecosystems (organ systems) within a larger biosphere (body), alterations in species stoichiometry (host cell types), resource cycling (cellular metabolism and cell-cell signaling), and ecosystem collapse (organ failure and death). In particular, as cancer cells generate their own ecosystem, displacing and co-opting normal cell function, resulting in systemic host (patient) effects that result in cytokine-mediated lethal syndromes that cause of majority of cancer patient deaths.
Citation Format: Kenneth James Pienta, Sarah R. Amend. The patient biosphere: Tumors live in people. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA27.
Abstract PR06: Metastatic latency and immune evasion mediated by autocrine WNT inhibition
Authors: Malladi Srinivas , Macalinao Danilo G. , Jin Xin , He Lan , Massague Joan 
Published: May 2019

Abstract
Metastasis frequently develops years after the removal of a primary tumor, from a minority of disseminated cancer cells that survived as latent entities through unknown mechanisms. We isolated latency competent cancer (LCC) cells from early-stage human lung and breast carcinomas and defined the mechanisms that prevent the outgrowth, support the long-term survival, and maintain the tumor-initiating potential of these cells during the latent metastasis stage. LCC cells show stem cell-like characteristics and express Sox transcription factors, which are essential for their survival in host organs under restrictive conditions and for metastatic outgrowth under permissive conditions. Through WNT inhibition, LCC cells self-impose a slow cycling state and evade immune clearance. By expressing a Sox-dependent stem-like state and actively silencing WNT signaling, LCC cells can enter quiescence and evade innate immunity to remain latent for extended periods.
Citation Format: Srinivas Malladi, Danilo G. Macalinao, Xin Jin, Lan He, Joan Massague. Metastatic latency and immune evasion mediated by autocrine WNT inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr PR06.
Abstract PR15: Haptotaxis and direct remodeling of the extracellular matrix by tumor cells is important for metastasis
Authors: Oudin Madeleine J. , Jonas Oliver , Kosciuk Tatiana , Broye Liliane , Wyckoff Jeff , Klazen Joelle , Lamar John , Asokan Sreeja , Whittaker Charlie , Langer Robert , Cima Michael , Wisinski Kari , Hynes Richard , Lauffenburger Douglas , Keely Patricia , Bear James , Gertler Frank 
Published: May 2019

Abstract
The tissue microenvironment, composed of stromal cells and extracellular matrix (ECM), is known to contribute to tumor progression, by providing both the structure and signals that promote tumor cell proliferation, survival and invasion. Fibronectin and collagen are major components of the tumor microenvironment, however, how tumor cells gain the ability to respond to these substrate-bound cues and how ECM sensing contributes to promoting metastasis remain poorly understood. Here, using a combination of in vitro and in vivo imaging, we show that gradients of FN can promote directional cell motility of breast cancer cells, a process dependent upon the actin regulatory Mena. Expression of the pro-metastatic isoform MenaINV allows cells to haptotax towards very high concentrations of FN, found near blood vessels and tumor periphery. Haptotaxis requires the direct interaction between α5β1 integrin and Mena/ MenaINV and is driven by outside-in signaling at focal complexes, crosstalk between α5β1 and EGFR, and inside-out tumor cell dependent ECM remodeling. These findings are clinically relevant as patients with high levels of MenaINV protein and FN have increased recurrence and decreased survival in two breast cancer cohorts. Our results identify a novel tumor cell-intrinsic mechanism that promotes ECM remodeling and directed migration, ultimately affecting metastasis.
Citation Format: Madeleine J. Oudin, Oliver Jonas, Tatiana Kosciuk, Liliane Broye, Jeff Wyckoff, Joelle Klazen, John Lamar, Sreeja Asokan, Charlie Whittaker, Robert Langer, Michael Cima, Kari Wisinski, Richard Hynes, Douglas Lauffenburger, Patricia Keely, James Bear, Frank Gertler. Haptotaxis and direct remodeling of the extracellular matrix by tumor cells is important for metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr PR15.
Treatment options for locked posterior shoulder dislocations and clinical outcomes
Authors: Aydin Nuri , Enes Kayaalp Mahmut , Asansu Mustafa , Karaismailoglu Bedri 
Published: May 2019

Posterior dislocations are rare and diagnostically difficult injuries. Diagnosis is often delayed and this leads to a locked posteriorly dislocated humeral head. Treatment options include conservative methods and surgical anatomic reconstruction options as well as non-anatomic surgical procedures such as subscapularis tendon transfer, hemiarthroplasty and total shoulder arthroplasty. Decision-making for treatment as well as prognosis depend on the extent of the articular defect size of the humeral head, duration of the dislocation and patient-specific conditions such as age and activity levels. Cite this article: EFORT Open Rev 2019;4:194-200. DOI: 10.1302/2058-5241.4.180043
Shortcomings in the evaluation of biomarkers in ovarian cancer: a systematic review
Authors: Olsen Maria , Ghannad Mona , Lok Christianne , Bossuyt Patrick M. 
Published: May 2019

Abstract

Background
Shortcomings in study design have been hinted at as one of the possible causes of failures in the translation of discovered biomarkers into the care of ovarian cancer patients, but systematic assessments of biomarker studies are scarce. We aimed to document study design features of recently reported evaluations of biomarkers in ovarian cancer.

Methods
We performed a systematic search in PubMed (MEDLINE) for reports of studies evaluating the clinical performance of putative biomarkers in ovarian cancer. We extracted data on study designs and characteristics.

Results
Our search resulted in 1026 studies; 329 (32%) were found eligible after screening, of which we evaluated the first 200. Of these, 93 (47%) were single center studies. Few studies reported eligibility criteria (17%), sampling methods (10%) or a sample size justification or power calculation (3%). Studies often used disjoint groups of patients, sometimes with extreme phenotypic contrasts; 46 studies included healthy controls (23%), but only five (3%) had exclusively included advanced stage cases.

Conclusions
Our findings confirm the presence of suboptimal features in clinical evaluations of ovarian cancer biomarkers. This may lead to premature claims about the clinical value of these markers or, alternatively, the risk of discarding potential biomarkers that are urgently needed.