bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1465: Radiosensitization of NSCLC through modulation of autophagy and senescence
Authors: Goehe Rachel W. , Sharma Khushboo , Maiti Aparna , Gewirtz David A. 
Published: August 2012

Abstract
Introduction: Radiotherapy (IR) is a key treatment modality in the treatment of patients with non-small cell lung cancer (NSCLC), and is commonly combined with chemotherapy to prolong survival, although the gain is generally quite modest. An underlying cause for the relatively poor cure rate is the resistance to chemotherapy, which is partially associated with the dysregulation of cell death signaling, particularly apoptotic pathways. Thus, the current work was designed to exploit the capacity of 1,25D3 (the hormonally active form of vitamin D) to radiosensitize A549 cells. Experimental Procedure: In vitro studies assessed the effects of 100nM 1,25D3 alone, radiation alone (6 Gy) and the combination treatment of 100nM 1,25D3 concurrently with radiation in A549 NSCLC cells. Cell viability was assessed over a period of 7 days and sensitization to radiation was confirmed by clonogenic survival assays. Senescence was measured by β-galactosidase staining as well as C12FDG fluorescence measurement by flow cytometry. Levels of the senescence associated markers p21, pRb, and p53 were monitored by western immunoblotting. Autophagy was inhibited pharmacologically using 5mM 3-MA and 10µM chloroquine. Autophagy induction was monitored by acridine orange with quantification using flow cytometry, while autophagic flux was based on degradation of p62. Results: 1,25D3 sensitized A549 cells to radiation based on reduced clonogenic survival; viable cell counting indicated that the combination treatment resulted in apparently irreversible growth arrest with no significant recovery. β-galactosidase staining, C12FDG measurement by flow cytometry, and p21 expression levels were indicative of senescence by Days 3 and 5 while acridine orange staining and p62 degradation demonstrated the induction of autophagy. Pharmacological suppression of autophagy induced by 1,25D3 + IR resulted in a temporary delay of senescence. Conclusions: For many years, cancer therapy has relied on cytotoxic treatment strategies for the eradication of tumors and overall patient survival. These therapies are associated with severe and often harmful side effects. Recent studies have suggested that therapy-induced senescence could provide an alternative strategy for improving cancer therapy. Our studies demonstrate that treatment with 1,25D3 has the capacity to sensitize A549 cells to radiation treatment by the induction of senescence that is preceded by autophagy. This model could represent a novel, pro-senescence therapy treatment to promote disease intervention and therapeutic gain for NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1465. doi:1538-7445.AM2012-1465
Abstract 1468: Cerium oxide nanoparticles sensitize pancreatic cancer cells to radiation by modulating the JNK pathway
Authors: Wason Melissa S. , Colon Jimmie , Zhao Jihe , Baker Cheryl H. 
Published: August 2012

Abstract
Pancreatic cancer, one of the most lethal cancers, has a poor prognosis and a high mortality rate. Currently, the absence of effective therapies increases reliance on radiation therapy (RT) to treat pancreatic cancer. We have previously reported that Cerium Oxide Nanoparticles (CONPs) are selectively toxic to cancer cells and possess the ability to selectively sensitize pancreatic cancer cells to radiation-induced cell death. Radiation-induced H2O2 production was significantly increased in the presence of less than or equal to 10 µM of CONPs and radiation-induced ROS production was increased in human L3.6pl pancreatic cancer cells pre-treated with 10 µM CONPs, which correlated with a significant decrease in cell viability and clonogenicity as compared to radiation alone. Conversely, ROS production was decreased in normal hTERT-HPNE pancreatic cells without impacting cell viability. The volume of pancreatic tumors was reduced by 48% in mice treated with combination therapy compared to radiation alone. Immunohistochemical (IHC) analysis revealed that combination therapy resulted in a significant increase in tumor cell apoptosis. In the most recent study, we determined the mechanism responsible for the increase in apoptosis as a result of increased ROS levels. L3.6pl cells (radiation sensitive), PANC-1 (radiation resistant) and HPNE (normal pancreatic cells) were treated with 5 Gy radiation in the presence or absence of 10 µM CONPs. CONPs selectively increased RT-induced Thioredoxin (TRX) oxidation in the cancer cells (L3.6pl: 14.2%, p&lt;0.001; PANC-1: 23.5%, p&lt;0.005) which correlated with a 35-40% increase in ASK-1 phosphorylation in both cell lines. Excitingly, western blot analyses showed a selective increase in JNK phosphorylation in both radiation sensitive (L3.6pl: JNK1 at 15%, JNK2 at 20%) and radiation resistant (PANC-1: JNK1 at 36%, JNK2 at 37%) cells which correlated with an increase in Caspase 3/7 activity (L3.6pl: 36.4%, p&lt;0.05; PANC-1: 43.1%, p&lt;0.05) compared to radiation alone. Knockdown of JNK expression by siRNA resulted in abrogation of Caspase 3/7 activity and corresponding cell death. Combination therapy of CONPs and radiation in an orthotopic murine model produced significant increases in JNK phosphorylation and Caspase 3 cleavage shown by IHC analysis. These data suggest that CONPs may act as a radiosensitizer in treatment of pancreatic cancer through the induction of JNK activation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1468. doi:1538-7445.AM2012-1468
Abstract 1478: Bone marrow mesenchymal stem cells suppress tumor cell apoptosis and are selectively recruited to early-stage tumors
Authors: Bergfeld Scott A. , Blavier Laurence , Moats Rex A. , DeClerck Yves A. 
Published: August 2012

Abstract
Bone marrow mesenchymal stem cells (BMMSC) are recruited to primary tumors and have been reported to display pro-tumorigenic as well as anti-tumorigenic activities. However, the mechanisms behind their effect on tumor development are still unclear. We have isolated murine bone marrow aspirates and plated them on fibronectin/collagen I, which allows expansion of an adherent stromal cell population in 3-6 weeks. These cells express the CD44 hyaluronic acid receptor in the absence of hematopoietic (CD34), myeloid (CD45), and endothelial (CD31/VEGFR2) markers and display both spontaneous and inducible adipogenesis/ osteoblastogenesis in culture. 3D matrigel cultures of murine 4T1 mammary carcinoma cells revealed enhanced generation of tumor spheroids in the presence of BMMSC or their conditioned media. Conditioned media from BMMSC also increased 4T1 cell expansion in 2D monolayer cultures, with loss of this phenomenon after heat inactivation suggesting the presence of protein-based signaling. Cell cycle analysis of 4T1 cells treated with BMMSC conditioned media revealed no statistically significant change in mitotic potential in either growth (serum present) or growth-arrest (serum depleted) phase, as determined by PI staining and BrdU uptake. However, analysis of apoptosis in 4T1 cells treated with BMMSC conditioned media showed increased percentages of live cells by PI uptake and AnnexinV staining, as well as a reduction in caspase-3 and caspase-9 activation by colorimetric assay, as the cells entered growth arrest phase. Furthermore, treatment with BMMSC conditioned media preserved viability in 4T1 cells exposed to paclitaxel under no-serum conditions. Complementary studies of BMMSC tumor-directed migration indicate that BMMSC show preferential in vitro recruitment by murine tumor cell lines which generate reactive stroma (4T1, LL/2 lung carcinoma) vs. no stroma (B16 melanoma). In vivo recruitment of BMMSC by early-stage/slow-growing subcutaneous 4T1 tumors was also visualized by bioluminescent imaging, red fluorescence, and magnetic resonance imaging of BMMSC labeled with iron-nanoparticles. These results were confirmed by immunohistochemical evaluation of iron deposits by Prussian blue stain and by immunofluorescent detection of PKH26-labeled BMMSC. Overall, our data identify BMMSC as an important mediator of tumor cell survival/treatment resistance and reveal an enhanced tropism of BMMSC toward early 4T1 tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1478. doi:1538-7445.AM2012-1478
Abstract 1482: Abnormal abundance of senescent fibroblasts in the tumor stroma of non-small cell lung cancer patients
Authors: Puig Marta , Lugo Roberto , Giménez Alícia , Galgoczy Roland , Genís Sandra , Ramírez Josep , Gómez-Caro Abel , Gascón Pere , Alcaraz Jordi , Reguart Noemi 
Published: August 2012

Abstract
Although permanent cell cycle arrest through senescence has been previously regarded as a protective mechanism against tumor growth, there is growing evidence that the abnormal abundance of senescent cells observed in the stroma of some types of cancer may support cancer progression. However, the presence of senescent cells in the tumor stroma of non-small cell lung cancer (NSCLC), which is a major cause of cancer death in western countries, remains poorly defined. To fill this gap of knowledge, we set up a bank of primary human lung fibroblasts isolated from both tumor-free regions and tumors of NSCLC patients diagnosed with adenocarcinoma (ADC, n=5), squamous cell carcinoma (SCC, n=5) or large cell carcinoma (LCC, n=2) histological subtypes. Tumor-associated fibroblasts (TAFs) or patient-matched control fibroblasts (NTAFs) were seeded in collagen-coated culture dishes in culture media supplemented with 10% serum for 3 days. The presence of senescent cells was assessed by examining senescent associated signatures including increased spreading, decreased proliferation, and the positive response to the beta-galactosidase (beta-gal) assay. The beta-gal assay was negative in &gt;90% of NTAFs (11/12). Likewise, TAFs from either ADC or SCC were negative for beta-gal assay in 80% of the patients examined (4/5), whereas &lt;10% of cells were positive for the beta-gal assay in the remaining 20% of patients. In contrast, beta-gal positive TAFs were observed in 100% of LCC patients (2/2), with an average of ∼50% positive TAFs per patient. In agreement with these findings, LCC TAFs were poorly or non-responsive to serum stimulation in terms of cell cycle progression as assessed by flow cytometry, unlike patient-matched LCC NTAFs. Moreover, LCC TAFs exhibited a high percentage of largely spread fibroblasts, which is commonly associated with the senescent phenotype. These preliminary results strongly suggest that the senescent phenotype is absent in normal fibroblasts, and abnormally and specifically present in lung fibroblasts from the tumor stroma of LCC patients, therefore revealing the presence of NSCLC-subtype specific alterations in the tumor microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1482. doi:1538-7445.AM2012-1482
Abstract 1489: The role of bone marrow adipocyte-induced HO-1 expression in prostate tumor survival in bone
Authors: Hardaway Aimalie L. , Herroon Mackenzie K. , Rajagurubandara Erandi N. , Turchick Audrey , Podgorski Izabela 
Published: August 2012

Abstract
Prostate cancer (PCa) is the second leading cause of cancer deaths among men in the United States. Obesity, adipocyte-derived signals, and adipose tissue inflammation are major contributors to development of aggressive PCa, with higher recurrence and higher mortality rates. Bone is a primary site of metastasis of PCa and obese and overweight men have a three-fold higher risk of progression to metastatic disease compared to normal-weight men receiving the same treatment. Experimental and clinical evidence indicate that bone marrow adipocyte numbers increase with age and obesity and their increased presence affects homeostasis in the bone microenvironment. It is not, however, currently known how adipocyte-derived factors influence tumor growth and survival in bone. Heme oxygenase 1 (HO-1) is a stress-responsive protein induced by hypoxia and inflammation, and it has been shown to play a role in prostate carcinogenesis and cell survival. Its role in tumor cell aggressiveness and survival in response to adipocyte-derived signals has not been previously explored. Here, we investigated the effects of bone marrow adipocyte-derived factors on HO-1/IL-1α pathway in PCa cells. Our study was driven by hypothesis that adipocytes increase invasiveness and survival of PCa cells via upregulation of HO-1. We utilized Taqman RT PCR analyses and western blotting approaches to demonstrate that levels of HO-1 and its inducer IL-1α increase in PC3, DU145 and C42B prostate cancer cell lines in response to treatment with adipocyte conditioned media (Adipo CM). Immunofluorescence analyses and subcellular fractionation methods were used to demonstrate a translocation of HO-1 from the cytoplasm to nucleus upon exposure to Adipo CM. Invasiveness of PCa cells in response to adipocyte-derived factors in the absence and presence of IL-1α neutralizing antibody and HO-1 inhibitor Zinc protoporphyrin IX was assessed using Boyden chamber assays. Studies are currently underway to determine the significance of HO-1/IL-1α upregulation in tumor cells survival and response to chemotherapy. Collectively, the results of our studies demonstrate that adipocyte-induced upregulation of HO-1/IL-1α pathways may be playing a significant role in promoting prostate tumor aggressiveness and survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1489. doi:1538-7445.AM2012-1489
Abstract 1491: Tumor-associated stromal cells increase malignancy of human colorectal cancers through epithelial-to-mesenchymal transition
Authors: Mele Valentina , Muraro Manuele Giuseppe , Calabrese Diego , Amatruda Nunzia , Amicarella Francesca , Zuber Markus , Bocelli-Tyndall Chiara , Martin Ivan , Terracciano Luigi Maria , Spagnoli Giulio Cesare , Iezzi Giandomenica 
Published: August 2012

Abstract
BACKGROUNDS & AIMS: Exogenously administered mesenchymal stromal cells (MSCs) have been shown to migrate into tumor tissues and contribute to tumor development. Still unclear is however, whether MSCs are actually a component of the stroma associated with primary tumors. The mechanisms underlying this interaction also remain to be characterized. Here we investigated the phenotype and functional properties of tumor-associated stromal cells (TASCs) isolated from human primary colorectal cancers (CRCs) and compared them with those derived from the bone marrow of healthy donors. METHODS: TASCs, isolated from CRC biopsies, and MSCs, derived from the bone marrow of healthy donors, were cultured with CRC cells from established cell lines. Proliferation, expression of epithelial-to-mesenchymal transition (EMT)-related genes and surface markers, and the release of soluble factors were evaluated. Tumorigenicity and invasive potential of CRC cells exposed to stromal cells were also investigated in vivo. RESULTS: TASCs expanded from CRC-associated stroma resembled MSCs in morphology and phenotype. Similar to MSCs, they enhanced tumor cell proliferation through the release of soluble factors, and induced upregulation of EMT-related genes on tumor cells in vitro through the expression of surface-bound TGF-beta. Conditioning by stromal cells resulted in accelerated tumor growth and increased invasiveness of CRC cells in vivo. CONCLUSIONS: The stroma associated to primary CRCs includes MSC-like cells capable of initiating EMT on CRC cells, thus contributing to tumor growth and spreading.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1491. doi:1538-7445.AM2012-1491
Abstract 1500: Bone morphogenetic proteins stimulate mammary fibroblasts to promote mammary tumorigenesis
Authors: Owens Philip , Polikowsky Hannah , Pickup Michael W. , Matise Lauren A. , Gorska Agnes E. , Shaw Aubie K. , Novitskiy Sergey V. , Aakre Mary E. , Hong Charles C. , Moses Harold L. 
Published: August 2012

Abstract
Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor ≤ (TGFβ) superfamily. BMPs have recently been shown to be overexpressed in human breast cancers, however loss of BMP signaling in mammary carcinomas has also been shown to accelerate metastases. Stimulation of dermal fibroblasts with BMP4 can enhance pro-tumorigenic factors uniquely from the epidermal response. Additionally, treatment of carcinoma-associated fibroblasts (CAFs) derived from a mouse prostate carcinoma with BMP have been reported to stimulate tumor-associated angiogenesis. We sought to determine the effect of BMP treatment on mammary fibroblasts and determine their response during mammary tumor progression. We first identified secreted pro-inflammatory cytokines and matrix-metalloproteinases (MMPs) upregulated in response to BMP4 treatment. We found that fibroblasts stimulated with BMP4 could enhance tumor invasion, which was inhibited by a BMP receptor kinase antagonist. We next demonstrated that BMP signaling was specifically absent in the stroma of human ductal and lobular carcinoma in situ (DCIS & LCIS). Yet after progression to invasion, breast tumors of many distinct subtypes contained a stroma active for BMP signaling. We further extended these observations with human normal mammary fibroblasts and compared them to human fibroblasts from breast cancer and found that BMP was capable of inducing MMP3 and IL-6 secretion in normal fibroblasts. However carcinoma associated fibroblasts had constitutively elevated levels of MMP3 and IL-6 that corresponded to enhanced BMP signaling in addition to loss of secreted BMP antagonists. These experiments demonstrate that BMP may play important tumor promoting functions within the tumor microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1500. doi:1538-7445.AM2012-1500
Abstract 1512: Sunitinib-induced metastasis is tumor dependent and is mediated by c-Met/HGF pathway
Authors: Shojaei Farbod , Simmons Brett H. , Lee Joseph H. , Lappin Patrick B. , Christensen James G. 
Published: August 2012

Abstract
Recent studies in several tumor models indicated that treatment with angiogenic inhibitors may trigger induction of metastasis to other organs. Here we investigated modes of resistance and invasion in several tumors including 4T1 (breast), H460 (lung) and Colo205 (colorectal) using sunitinib at doses comparable to clinically utilized regimen. In comparison with vehicle-treated tumors, sunitinib increased metastasis to lung in 4T1 tumors and to peritoneal lymph node in Colo205 tumors. However, the same treatment did not induce invasiveness in H460 tumors, further suggesting that accelerating metastasis during treatment with angiogenic inhibitors is tumor dependent. Interestingly, Crizotinib (a dual inhibitor of c-Met and ALK pathways) as single agent or in combination with sunitinib reduced metastasis in all models tested suggesting a role for c-Met/HGF pathway in intrinsic- or sunitinib-induced -metastasis. Moreover, ELISA data showed that while c-Met is highly enriched in tumor cells, HGF is secreted mainly by the stroma (mouse HGF) suggesting a paracrine fashion for c-Met pathway activation in the tumors. In conclusion, our findings indicate that sunitinib-induced metastasis is tumor dependent and further supports a rationale for combination of anti-angiogenesis and c-Met inhibition in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1512. doi:1538-7445.AM2012-1512
Abstract 1514: The Warburg effect in stromal cells drives breast cancer cell plasticity via interleukin 6
Authors: Sansone Pasquale , Ceccarelli Claudio , Storci Gianluca , Berishaj Marjan , Cricca Monica , Chang Qing , Santini Donatella , Bonafe Massimiliano , Bromberg Jacqueline 
Published: August 2012

Abstract
Background: Intra-tumoral heterogeneity is an emerging concept in breast cancer biology. This concept entails the notion that sub-populations within the tumor possess different biologic features and hence vary in sensitivity to therapies. The inhibition of estrogen receptor alpha (ER), a hormone based therapy (HT), is a successful therapy for luminal A breast cancer patients. However, HT resistance, due to a variety of factors such as the tumor microenvironment, plays a crucial role in breast cancer progression. Genetic alterations in the stromal fibroblasts, such as deficiency for the tumor-suppressors (TP53 and pRB) within the tumor microenvironment, are associated with poor prognosis in breast cancer. Hypothesis: We propose that stromal cells promote the intra-tumoral heterogeneity in luminal A breast cancer. We developed an in vivo model to study the crosstalk between bone marrow stromal cells (HS27) immortalized with human papilloma virus (HPV) E6 onco-protein and a luminal A breast cancer cell line, MCF-7. Results: Here we report that HS27 cells secrete high amounts of IL-6, which operates in an autocrine and paracrine fashion. Paracrine IL-6 from HS27 cells contributes to MCF-7 cancer cell dissemination and metastasis. Autocrine IL-6 drives anaerobic glycolysis (Warburg effect) and produces high levels of lactate and H+ from HS27 cells. High levels of IL-6 and lactate from the conditioned media of HS27 cells promote the expansion of a MCF-7 cells sub-population expressing high levels of lactate shuttle MCT-1 and low levels of ER. This cancer cell population exhibits invasive and metastatic potential. Finally, we show that HPV DNA positive breast cancer lesions are more biologically aggressive, and express higher levels of IL-6, than negative ones. Conclusion: This study highlights that tumor microenvironment stressors (viral infections and oncogenes) promote a complex metabolic crosstalk (anaerobic glycolysis and oxidative phosphorylation) between stroma and cancer cells, ultimately sustaining cancer progression. Grant support: DOD W81XWH-10-1-1033 to PS, NIH R01 CA87637 to JB, PRIN KTRN38 2008 to MB
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1514. doi:1538-7445.AM2012-1514