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intratumor heterogeneity

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https://www.readbyqxmd.com/read/28108516/fibrinolytic-enzyme-co-therapy-improves-tumor-perfusion-and-therapeutic-efficacy-of-anticancer-nanomedicine
#1
Ameya R Kirtane, Tanmoy Sadhukha, Hyunjoon Kim, Vidhi Khanna, Brenda Koniar, Jayanth Panyam
Elevated interstitial fluid pressure and solid stress within tumors contribute to poor intratumoral distribution of nanomedicine. In this study, we hypothesized that the presence of fibrin in tumor extracellular matrix contributes to hindered intratumoral distribution of nanocarriers and that this can be overcome through the use of a fibrinolytic enzyme such as tissue plasminogen activator (tPA). Analysis of fibrin expression in human tumor biopsies showed significant fibrin staining in nearly all tumor types evaluated...
January 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28098570/preferential-localization-of-met-expression-at-the-invasion-front-and-in-spreading-cells-through-air-spaces-in-non-small-cell-lung-carcinomas
#2
Camille Lapère, Alexis B Cortot, Valérie Grégoire, Vincent Cockenpot, David Tulasne, Marie-Christine Copin
The involvement of the HGF/MET pathway in acquisition of an invasive phenotype in non-small cell lung carcinomas (NSCLCs) suggests that MET inhibitors might prove effective against these cancers, but clinical trials have yielded conflicting results. The aim of our study was to evaluate how intratumoral heterogeneity (ITH) of MET staining affects the determination of MET status for therapeutic purposes. We analyzed 64 NSCLC samples, including 33 adenocarcinomas (ADCs) and 31 squamous cell carcinomas (SCCs). We used immunohistochemistry to detect MET and phospho-MET on whole slides and determined the MET SP44 immunoscore and the H-score...
January 16, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28092682/limited-heterogeneity-of-known-driver-gene-mutations-among-the-metastases-of-individual-patients-with-pancreatic-cancer
#3
Alvin P Makohon-Moore, Ming Zhang, Johannes G Reiter, Ivana Bozic, Benjamin Allen, Deepanjan Kundu, Krishnendu Chatterjee, Fay Wong, Yuchen Jiao, Zachary A Kohutek, Jungeui Hong, Marc Attiyeh, Breanna Javier, Laura D Wood, Ralph H Hruban, Martin A Nowak, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Christine A Iacobuzio-Donahue
The extent of heterogeneity among driver gene mutations present in naturally occurring metastases-that is, treatment-naive metastatic disease-is largely unknown. To address this issue, we carried out 60× whole-genome sequencing of 26 metastases from four patients with pancreatic cancer. We found that identical mutations in known driver genes were present in every metastatic lesion for each patient studied. Passenger gene mutations, which do not have known or predicted functional consequences, accounted for all intratumoral heterogeneity...
January 16, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28073839/unsupervised-clustering-of-quantitative-image-phenotypes-reveals-breast-cancer-subtypes-with-distinct-prognoses-and-molecular-pathways
#4
Jia Wu, Yi Cui, Xiaoli Sun, Guohong Cao, Bailiang Li, Debra M Ikeda, Allison W Kurian, Ruijiang Li
PURPOSE: To identify novel breast cancer subtypes by extracting quantitative imaging phenotypes of the tumor and surrounding parenchyma, and to elucidate the underlying biological underpinnings and evaluate the prognostic capacity for predicting recurrence-free survival (RFS). METHODS: We retrospectively analyzed dynamic contrast-enhanced magnetic resonance imaging data of patients from a single-center discovery cohort (n=60) and an independent multi-center validation cohort (n=96)...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28073006/bcl9l-dysfunction-impairs-caspase-2-expression-permitting-aneuploidy-tolerance-in-colorectal-cancer
#5
Carlos López-García, Laurent Sansregret, Enric Domingo, Nicholas McGranahan, Sebastijan Hobor, Nicolai Juul Birkbak, Stuart Horswell, Eva Grönroos, Francesco Favero, Andrew J Rowan, Nicholas Matthews, Sharmin Begum, Benjamin Phillimore, Rebecca Burrell, Dahmane Oukrif, Bradley Spencer-Dene, Michal Kovac, Gordon Stamp, Aengus Stewart, Havard Danielsen, Marco Novelli, Ian Tomlinson, Charles Swanton
Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling...
January 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28068934/concordance-between-pik3ca-mutations-in-endoscopic-biopsy-and-surgically-resected-specimens-of-esophageal-squamous-cell-carcinoma
#6
Ken Hatogai, Satoshi Fujii, Takashi Kojima, Hiroyuki Daiko, Toshihiko Doi, Atsushi Ohtsu, Atsushi Ochiai, Yuichi Takiguchi, Takayuki Yoshino
BACKGROUND: PIK3CA mutations are expected to be potential therapeutic targets for esophageal squamous cell carcinoma (ESCC). We aimed to clarify the concordance between PIK3CA mutations detected in endoscopic biopsy specimens and corresponding surgically resected specimens. METHODS: We examined five hotspot mutations in the PIK3CA gene (E542K, E545K, E546K, H1047R, and H1047L) in formalin-fixed and paraffin-embedded tissue sections of paired endoscopic biopsy and surgically resected specimens from 181 patients undergoing curative resection for ESCC between 2000 and 2011 using a Luminex technology-based multiplex gene mutation detection kit...
January 9, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28062830/dissecting-inherent-intratumor-heterogeneity-in-patient-derived-glioblastoma-culture-models
#7
Jian Teng, Cintia Carla da Hora, Rami S Kantar, Ichiro Nakano, Hiroaki Wakimoto, Tracy T Batchelor, E Antonio Chiocca, Christian E Badr, Bakhos A Tannous
BACKGROUND: Molecular profile of glioblastoma multiforme (GBM) revealed 4 subtypes, 2 of which, proneural and mesenchymal, have been predominantly observed, with the latter displaying a more aggressive phenotype and increased therapeutic resistance. Single-cell RNA sequencing revealed that multiple subtypes actually reside within the same tumor, suggesting cellular heterogeneity in GBM. Further, plasticity between these 2 subtypes is observed during tumor recurrence and in response to radiation therapy...
January 6, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28062556/the-cellular-origin-and-evolution-of-breast-cancer
#8
Mei Zhang, Adrian V Lee, Jeffrey M Rosen
In this review, we will discuss how the cell of origin may modulate breast cancer intratumoral heterogeneity (ITH) as well as the role of ITH in the evolution of cancer. The clonal evolution and the cancer stem cell (CSC) models, as well as a model that integrates clonal evolution with a CSC hierarchy, have all been proposed to explain the development of ITH. The extent of ITH correlates with clinical outcome and reflects the cellular complexity and dynamics within a tumor. A unique subtype of breast cancer, the claudin-low subtype that is highly resistant to chemotherapy and most closely resembles mammary epithelial stem cells, will be discussed...
January 6, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28059585/initiation-of-aberrant-dna-methylation-patterns-and-heterogeneity-in-precancerous-lesions-of-human-hepatocellular-cancer
#9
Ryan A Hlady, Dan Zhou, William Puszyk, Lewis R Roberts, Chen Liu, Keith D Robertson
While intratumor heterogeneity contributes to disease progression, metastasis, and resistance to chemotherapy, it also provides a route to understanding the evolution and drivers of disease. Defects in epigenetic landscapes are intimately linked to pathogenesis of a variety of human diseases, with epigenetic deregulation promoting tumorigenesis. Understanding epigenetic heterogeneity is crucial in hepatocellular carcinoma (HCC), where epigenetic alterations are frequent, early, and pathogenic events. We determined genome-wide DNA methylation and copy number variation leveraging the Infinium 450 K in a series of regenerative nodules from within single patient livers...
January 6, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28053020/blocking-tumor-educated-msc-paracrine-activity-halts-osteosarcoma-progression
#10
Serena Rubina Baglio, Tonny Lagerweij, Maria Pérez Lanzón, Dung Xuan Ho, Nicolas Léveillé, Sonia A Melo, Anne-Marie Cleton-Jansen, Ekaterina S Jordanova, Laura Roncuzzi, Michelina Greco, Monique A J van Eijndhoven, Giulia Grisendi, Massimo Dominici, Roberta Bonafede, Sinead Lougheed, Tanja D de Gruijl, Nicoletta Zini, Silvia Cervo, Agostino Steffan, Vincenzo Canzonieri, Aare Martson, Katre Maasalu, Sulev Koks, Thomas Wurdinger, Nicola Baldini, Dirk M Pegtel
PURPOSE: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets. EXPERIMENTAL DESIGN: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma we evaluated the effect of tumor extracellular vesicle (EV)-educated mesenchymal stem cells (TEMSCs) on osteosarcoma progression...
January 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28049185/correction-from-the-core-to-beyond-the-margin-a-genomic-picture-of-glioblastoma-intratumor-heterogeneity
#11
Marc Aubry, Marie de Tayrac, Amandine Etcheverry, Anne Clavreul, Stéphan Saikali, Philippe Menei, Jean Mosser
No abstract text is available yet for this article.
October 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/28047393/su-f-r-28-correction-of-fch-pet-bladder-uptake-using-virtual-sinograms-and-investigation-of-its-impact-on-the-quantification-of-prostate-textural-characteristics
#12
S Laberge, J Beauregard, L Archambault
PURPOSE: Textural biomarkers as a tool for quantifying intratumoral heterogeneity hold great promise for diagnosis and early assessment of treatment response in prostate cancer. However, spill-in counts from the bladder uptake are suspected to have an impact on the textural measurements of the prostate volume. This work proposes a correction method for the FCh-PET bladder uptake and investigates its impact on intraprostatic textural properties. METHODS: Two patients with PC received pre-treatment dynamic FCh-PET scans reconstructed at four time points (interval: 2 min), for which prostate and bladder contours were obtained...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28040204/molecular-approaches-for-classifying-endometrial-carcinoma
#13
REVIEW
Josep M Piulats, Esther Guerra, Marta Gil-Martín, Berta Roman-Canal, Sonia Gatius, Rebeca Sanz-Pamplona, Ana Velasco, August Vidal, Xavier Matias-Guiu
Endometrial carcinoma is the most common cancer of the female genital tract. This review article discusses the usefulness of molecular techniques to classify endometrial carcinoma. Any proposal for molecular classification of neoplasms should integrate morphological features of the tumors. For that reason, we start with the current histological classification of endometrial carcinoma, by discussing the correlation between genotype and phenotype, and the most significant recent improvements. Then, we comment on some of the possible flaws of this classification, by discussing also the value of molecular pathology in improving them, including interobserver variation in pathologic interpretation of high grade tumors...
December 28, 2016: Gynecologic Oncology
https://www.readbyqxmd.com/read/28029661/multiple-drug-resistance-associated-protein-mrp4-exports-prostaglandin-e2-pge2-and-contributes-to-metastasis-in-basal-triple-negative-breast-cancer
#14
Tyler J Kochel, Jocelyn C Reader, Xinrong Ma, Namita Kundu, Amy M Fulton
Cyclooxygenase-2 (COX-2) and its primary enzymatic product, prostaglandin E2 (PGE2), are associated with a poor prognosis in breast cancer. In order to elucidate the factors contributing to intratumoral PGE2 levels, we evaluated the expression of COX-2/PGE2 pathway members MRP4, the prostaglandin transporter PGT, 15-PGDH (PGE2 metabolism), the prostaglandin E receptor EP4, COX-1, and COX-2 in normal, luminal, and basal breast cancer cell lines. The pattern of protein expression varied by cell line reflecting breast cancer heterogeneity...
December 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/28012035/effective-downsizing-but-enhanced-intratumoral-heterogeneity-following-neoadjuvant-sorafenib-in-patients-with-non-metastatic-renal-cell-carcinoma
#15
Gencay Hatiboglu, Markus Hohenfellner, Aysenur Arslan, Boris Hadaschik, Dogu Teber, Jan Philipp Radtke, Peter Hallscheidt, Yanis Tolstov, Wilfried Roth, Carsten Grüllich, Johannes Huesing, Stefan Duensing, Sascha Pahernik
OBJECTIVES: To evaluate the safety and feasibility of sorafenib prior to surgery for downsizing tumors in patients with non-metastatic cT1-3 renal tumors together with a characterization of functional intratumoral heterogeneity (ITH). MATERIALS AND METHODS: The effects of 4-week sorafenib prior to curative surgery were assessed in a prospective, single-center, randomized, placebo-controlled, double-blinded, pilot trial in patients with T1-3N0M0 renal cell carcinoma (RCC)...
December 23, 2016: Langenbeck's Archives of Surgery
https://www.readbyqxmd.com/read/28007624/capture-based-targeted-ultra-deep-sequencing-in-paired-tissue-and-plasma-samples-demonstrates-differential-subclonal-ctdna-releasing-capability-in-advanced-lung-cancer
#16
Xiaowei Mao, Zhou Zhang, Xiaoxuan Zheng, Fangfang Xie, Feidie Duan, Liyan Jiang, Shannon Chuai, Han Han-Zhang, Baohui Han, Jiayuan Sun
INTRODUCTION: Circulating tumor DNA (ctDNA), representing an unbiased way to assess tumor genetic profile non-invasively, facilitates studying intratumor heterogeneity. Although intratumor heterogeneity has been elucidated substantially in a few cancer types, including non-small cell lung cancer (NSCLC), how it influences the ability of tumor cells harboring different genetic abnormalities in releasing their DNA remains elusive. We designed a capture-based panel targeting NSCLC to detect and quantify genetic alterations from plasma using deep sequencing...
December 19, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27999739/tlr7-based-cancer-immunotherapy-decreases-intratumoral-myeloid-derived-suppressor-cells-and-blocks-their-immunosuppressive-function
#17
Thibaud Spinetti, Lorenzo Spagnuolo, Inès Mottas, Chiara Secondini, Marina Treinies, Curzio Rüegg, Christian Hotz, Carole Bourquin
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with the capacity to inhibit immunological responses. During cancer progression, MDSC are recruited to the tumor sites and secondary lymphoid organs, leading to the suppression of the antitumor function of NK and T cells. Here, we show that the TLR7/8 agonist resiquimod (R848) has a direct effect on MDSC populations in tumor-bearing mice. Systemic application of R848 led to a rapid reduction in both intratumoral and circulating MDSC...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27994939/pointwise-mutual-information-quantifies-intratumor-heterogeneity-in-tissue-sections-labeled-with-multiple-fluorescent-biomarkers
#18
Daniel M Spagnolo, Rekha Gyanchandani, Yousef Al-Kofahi, Andrew M Stern, Timothy R Lezon, Albert Gough, Dan E Meyer, Fiona Ginty, Brion Sarachan, Jeffrey Fine, Adrian V Lee, D Lansing Taylor, S Chakra Chennubhotla
BACKGROUND: Measures of spatial intratumor heterogeneity are potentially important diagnostic biomarkers for cancer progression, proliferation, and response to therapy. Spatial relationships among cells including cancer and stromal cells in the tumor microenvironment (TME) are key contributors to heterogeneity. METHODS: We demonstrate how to quantify spatial heterogeneity from immunofluorescence pathology samples, using a set of 3 basic breast cancer biomarkers as a test case...
2016: Journal of Pathology Informatics
https://www.readbyqxmd.com/read/27994520/evaluation-of-breast-cancer-stem-cells-and-intratumor-stemness-heterogeneity-in-triple-negative-breast-cancer-as-prognostic-factors
#19
Fang Yang, Lulu Cao, Zijia Sun, Juan Jin, Hehui Fang, Wenwen Zhang, Xiaoxiang Guan
Triple-negative breast cancer (TNBC) is a tumor subtype with aggressive behavior and poor clinical outcome for lacking effective therapies. Breast cancer stem cells (BCSCs) have been suggested to have tumor-initiating properties, but it remains unclear whether their presence contributes to the increased aggressiveness and poor prognosis of TNBC. Also, the breast cancers display frequent inter- and intra-tumor heterogeneity, which adds the complexity in diagnosis and predicting prognosis. Here we investigated the clinical relevance and prognostic value of the BCSC markers, CD44(+)/CD24(-), aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and CD133 in 88 TNBC cases...
2016: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/27974212/clonal-variation-in-drug-and-radiation-response-among-glioma-initiating-cells-is-linked-to-proneural-mesenchymal-transition
#20
Anna Segerman, Mia Niklasson, Caroline Haglund, Tobias Bergström, Malin Jarvius, Yuan Xie, Ann Westermark, Demet Sönmez, Annika Hermansson, Marianne Kastemar, Zeinab Naimaie-Ali, Frida Nyberg, Malin Berglund, Magnus Sundström, Göran Hesselager, Lene Uhrbom, Mats Gustafsson, Rolf Larsson, Mårten Fryknäs, Bo Segerman, Bengt Westermark
Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuum of multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers...
December 13, 2016: Cell Reports
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