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Tumor dormancy

Li-Yuan Yu-Lee, Guoyu Yu, Yu-Chen Lee, Song-Chang Lin, Jing Pan, Tianhong Pan, Kai-Jie Yu, Bin Liu, Chad J Creighton, Jaime Rodriguez-Canales, Pamela Andrea Villalobos, Ignacio Ivan Wistuba, Eulàlia de Nadal, Francesc Posas, Gary E Gallick, Sue-Hwa Lin
Bone metastasis from prostate cancer (PCa) can occur years after prostatectomy, due to reactivation of dormant disseminated tumor cells (DTC) in the bone, yet the mechanism by which DTC are initially induced into a dormant state in the bone remains to be elucidated. We show here that the bone microenvironment confers dormancy to C4-2B4 PCa cells, as they become dormant when injected into mouse femurs but not under the skin. Live-cell imaging of dormant cells at the single cell level revealed that conditioned medium from differentiated, but not undifferentiated osteoblasts induced C4-2B4 cellular quiescence, suggesting that differentiated osteoblasts present locally around the tumor cells in the bone conferred dormancy to PCa cells...
March 7, 2018: Cancer Research
Hussein F Aqbi, Matthew Wallace, Samay Sappal, Kyle K Payne, Masoud H Manjili
Tumor immunoediting consisting of three phases of elimination, equilibrium or dormancy, and escape has been supported by preclinical and clinical data. A comprehensive understanding of the molecular mechanisms by which antitumor immune responses regulate these three phases are important for developing highly tailored immunotherapeutics that can control cancer. To this end, IFN-γ produced by Th1 cells, cytotoxic T cells, NK cells, and NKT cells is a pleiotropic cytokine that is involved in all three phases of tumor immunoediting, as well as during inflammation-mediated tumorigenesis processes...
February 22, 2018: Journal of Leukocyte Biology
Gianluca Colella, Flavio Fazioli, Michele Gallo, Annarosaria De Chiara, Gaetano Apice, Carlo Ruosi, Amelia Cimmino, Filomena de Nigris
Cancer treatment is rapidly evolving toward personalized medicine, which takes into account the individual molecular and genetic variability of tumors. Sophisticated new in vitro disease models, such as three-dimensional cell cultures, may provide a tool for genetic, epigenetic, biomedical, and pharmacological research, and help determine the most promising individual treatment. Sarcomas, malignant neoplasms originating from mesenchymal cells, may have a multitude of genomic aberrations that give rise to more than 70 different histopathological subtypes...
February 21, 2018: International Journal of Molecular Sciences
Ilaria Roato, Riccardo Ferracini
Tumor mass is constituted by a heterogeneous group of cells, among which a key role is played by the cancer stem cells (CSCs), possessing high regenerative properties. CSCs directly metastasize to bone, since bone microenvironment represents a fertile environment that protects CSCs against the immune system, and maintains their properties and plasticity. CSCs can migrate from the primary tumor to the bone marrow (BM), due to their capacity to perform the epithelial-to-mesenchymal transition. Once in BM, they can also perform the mesenchymal-to-epithelial transition, allowing them to proliferate and initiate bone lesions...
February 20, 2018: Cancers
Xue Liang, Jia Gu, TongJuan Li, Lei Zhao, Xing Fu, Wei Zhang, Jue Wang, Zhen Shang, Wei Huang, Jianfeng Zhou
PAX5 mutations have important role in leukemogenesis and leukemia relapse, cancer cell dormancy participates in cancer relapse, but there was no report about PAX5 mutation inducing cancer cell dormancy. we constructed the PAX5 deletion Raji cell lines using gene editing technology, evaluated dormancy biological characteristics of cell lines. Our results showed PAX5 haploinsufficiency restrained the proliferation of Raji cells, induced G0/G1 arrest of Raji cells, reduced chemotherapy sensitivity. The tumor formation rate reduced in PAX5 mutation Raji cells...
February 14, 2018: Experimental Cell Research
Siriporn Keeratichamroen, Kriengsak Lirdprapamongkol, Jisnuson Svasti
It is now widely accepted that the tumor microenvironment influences the fate of cancer cells and plays crucial roles in regulating tumor dormancy and chemoresistance. The standard cell culture system on plastic surfaces does not account for cell interactions with the extracellular matrix (ECM), and is thus a less reliable approach to analyze cellular activity ex vivo. In the present study, A549 lung cancer cells were cultured in a semi-solid growth substrate (Matrigel) to mimic the tumor microenvironment and to investigate the role played by ECM proteins, as well as to evaluate the mechanism of cell-ECM communication...
February 12, 2018: Oncology Reports
Yuying Liu, Jiadi Lv, Jinyan Liu, Xiaoyu Liang, Xun Jin, Jing Xie, Le Zhang, Degao Chen, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Qingzhu Jia, Bo Zhu, Yan Kong, Jun Guo, Haizeng Zhang, Zhuo-Wei Hu, Xuetao Cao, F Xiao-Feng Qin, Bo Huang
Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell-intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27-dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models...
February 12, 2018: Journal of Clinical Investigation
Suruchi Mittal, Nicola J Brown, Ingunn Holen
Numerous clinical and pre-clinical studies have provided ample evidence supporting that the tumor microenvironment plays a significant role during breast cancer development, progression and in determining the therapeutic response. Areas covered: This review focuses on the evolving concept of the microenvironment as the critical participant in each step of the multi-stage process of malignant progression. Currently, only a small number of molecules form part of routine molecular diagnostics in breast caner, but microenvironment-derived biomarkers are potential additions to existing predictive and prognostic marker panels...
February 9, 2018: Expert Review of Molecular Diagnostics
Masoud H Manjili
In the past decades, a variety of strategies have been explored to cure cancer by means of immunotherapy, which is less toxic compared with chemotherapy or radiation therapy, and could establish memory for long-lasting protection against tumor recurrence. These endeavors have been successful in offering therapeutic antibodies, vaccines, or cellular immunotherapies, which resulted in prolonging survival of some cancer patients; however, complete cures have not been consistently achieved. The conception, design, and implementation of these promising immunotherapeutic strategies have been influenced by two schools of thought in immunology, which include the "self-nonself" (SNS) model and the "danger" model...
2018: Advances in Cancer Research
Geraldine Gueron, Nicolás Anselmino, Paula Chiarella, Emiliano G Ortiz, Sofia Lage Vickers, Alejandra V Paez, Jimena Giudice, Mario D Contin, Daiana Leonardi, Felipe Jaworski, Verónica Manzano, Ariel Strazza, Daniela R Montagna, Estefania Labanca, Javier Cotignola, Norma D Accorso, Anna Woloszynska-Read, Nora Navone, Roberto P Meiss, Raúl Ruggiero, Elba Vazquez
An abrupt increase in metastatic growth as a consequence of the removal of primary tumors suggests that the concomitant resistance (CR) phenomenon might occur in human cancer. CR occurs in murine tumors and ROS-damaged phenylalanine, meta-tyrosine (m-Tyr), was proposed as the serum anti-tumor factor primarily responsible for CR. Herein, we demonstrate for the first time that CR happens in different experimental human solid tumors (prostate, lung anaplastic, and nasopharyngeal carcinoma). Moreover, m-Tyr was detected in the serum of mice bearing prostate cancer (PCa) xenografts...
February 2, 2018: Cell Death & Disease
Margie N Sutton, Hailing Yang, Gilbert Y Huang, Caroline Fu, Michael Pontikos, Yan Wang, Weiqun Mao, Lan Pang, Maojie Yang, Jinsong Liu, Jan Parker-Thornburg, Zhen Lu, Robert C Bast
Among the 3 GTPases in the DIRAS family, DIRAS3/ARHI is the best characterized. DIRAS3 is an imprinted tumor suppressor gene that encodes a 26-kDa GTPase that shares 60% homology to RAS and RAP. DIRAS3 is downregulated in many tumor types, including ovarian cancer, where re-expression inhibits cancer cell growth, reduces motility, promotes tumor dormancy and induces macroautophagy/autophagy. Previously, we demonstrated that DIRAS3 is required for autophagy in human cells. Diras3 has been lost from the mouse genome during evolutionary re-arrangement, but murine cells can still undergo autophagy...
January 25, 2018: Autophagy
Jean-François Spinella, Chantal Richer, Pauline Cassart, Manon Ouimet, Jasmine Healy, Daniel Sinnett
Childhood acute lymphoblastic leukemia (cALL) is the most frequent pediatric cancer. Refractory/relapsed cALL presents a survival rate of ∼45% and is still one of the leading causes of death by disease among children. Mechanisms, such as clonal competition and evolutionary adaptation, govern treatment resistance. However, the underlying clonal dynamics leading to multiple relapses and differentiating early (<36 months postdiagnosis) from late relapse events remain elusive. Here, we use an integrative genome-based analysis combined with serial sampling of relapsed tumors (from primary tumor to ≤4 relapse events) from 19 pre-B-cell cALL patients (8 early and 11 late relapses) to assess the fitness of somatic mutations and infer their ancestral relationships...
February 13, 2018: Blood Advances
Amanda M Clark, Manu Kumar, Sarah Wheeler, Carissa Young, Raman Venkataramanan, Donna Stolz, Linda Griffith, Douglas A Lauffenburger, Alan Wells
Breast cancer mortality predominantly results from dormant micrometastases that emerge as fatal outgrowths years after initial diagnosis. In order to gain insights concerning factors associated with emergence of liver metastases, we recreated spontaneous dormancy in an all-human ex vivo hepatic microphysiological system (MPS). Seeding this MPS with small numbers (<0.05% by cell count) of the aggressive MDA-MB-231 breast cancer cell line, two populations formed: actively proliferating ('growing'; EdU+), and spontaneously quiescent ('dormant'; EdU-)...
January 20, 2018: Molecular & Cellular Proteomics: MCP
Syed Ammer Shah, Melika Zarei, Saeed H Manjili, Georgi Guruli, Xiang-Yang Wang, Masoud H Manjili
Immunotherapeutic targeting of advanced stage cancers has prolonged the survival of cancer patients, yet its curative efficacy is limited due to tumor immunoediting and escape. On the other hand, human vaccines have been able to eradicate smallpox and control several other infectious diseases. The success has resulted from the administration of vaccines in prophylactic settings, or during latency periods in order to protect an individual during future exposure to the disease rather than curing an established disease...
September 2017: Immunotherapy
Leonid Hanin, Jason Rose
We study metastatic cancer progression through an extremely general individual-patient mathematical model that is rooted in the contemporary understanding of the underlying biomedical processes yet is essentially free of specific biological assumptions of mechanistic nature. The model accounts for primary tumor growth and resection, shedding of metastases off the primary tumor and their selection, dormancy and growth in a given secondary site. However, functional parameters descriptive of these processes are assumed to be essentially arbitrary...
January 4, 2018: Bulletin of Mathematical Biology
Krishna C Vallabhaneni, Patrice Penfornis, Fei Xing, Yoni Hassler, Kristen V Adams, Yin-Yuan Mo, Kounosuke Watabe, Radhika Pochampally
Mesenchymal stromal cells (hMSCs) have been used to understand the stromal cell properties in solid tumors because of their ablity to differentiate into most cell types. We investigated the role of EVs from hMSCs (hMSC-EVs) in breast cancer metastasis using MDA-MB-231 parental cell line and organotropic sub-lines. We demonstrated that hMSC-EVs significantly suppressed the metastatic potential of the parental cell line when compared to their organotropic sublines. hMSC-EVs induce dormancy in the parental cell line but not in their organotropic sub-lines and miR-205 and miR-31 from EV cargo played a role...
December 15, 2017: Oncotarget
Vivian Adamski, Annika Hempelmann, Charlotte Flüh, Ralph Lucius, Michael Synowitz, Kirsten Hattermann, Janka Held-Feindt
Cellular dormancy is defined as a state in which cells enter quiescence driven by intrinsic or extrinsic factors, and striking parallels exist between the concept of cellular dormancy in malignancies and the cancer stem cell theory. We showed now that the proven dormancy markers insulin-like growth factor-binding protein 5, ephrin receptor A5 and histone cluster 1 H2B family member K were expressed in human glioblastomas in situ, were located in single tumor cells, and could be co-stained with each other and with the stem cell markers krüppel-like factor 4, octamer binding transcription factor 4 and sex determining region Y-box 2...
December 8, 2017: Oncotarget
Lamiaa El-Shennawy, Oleksii Dubrovskyi, Irida Kastrati, Jeanne M Danes, Yiqun Zhang, Herbert E Whiteley, Chad J Creighton, Jonna Frasor
A growing body of evidence suggests that the inflammatory NFκB pathway is associated with the progression of ER+ tumors to more aggressive stages. However, it is unknown whether NFκB is a driver or a consequence of aggressive ER+ disease. To investigate this question, we developed breast cancer cell lines expressing an inducible, constitutively active form of IκB kinase β (CA-IKKβ), a key kinase in the canonical NFκB pathway. We found that CA-IKKβ blocked E2-dependent cell proliferation in vitro and tumor growth in vivo in a reversible manner, suggesting that IKKβ may contribute to tumor dormancy and recurrence of ER+ disease...
February 15, 2018: Cancer Research
Vivian Chua, Andrew E Aplin
PURPOSE OF REVIEW: Currently, there are no U.S. Food and Drug Administration-approved or effective treatment options for advanced-stage uveal melanoma. In this article, we focus on therapeutic targets in pathways/mechanisms associated with common mutations in uveal melanoma. We review the challenges associated with targeting of these pathways and novel treatment strategies. RECENT FINDINGS: Common mutations that promote uveal melanoma initiation and progression include alterations in G protein subunit alpha q/11 (GNAQ/GNA11) and breast cancer gene 1-associated protein 1 (BAP1)...
March 2018: Current Opinion in Oncology
Mark R Wick
The metastasis of neoplastic cells from their site of origin to distant anatomic locations continues to be the principal cause of death from malignant tumors, and that fact has been recognized by physicians for over a century. After the work done by Halsted in the treatment of breast cancer in the 1880s, accepted surgical canon held that metastasis occurred in a linear fashion, with centrifugal "growth in continuity" from the primary neoplasm that first involved regional lymph nodes. Those structures were considered to then be the sources of more distant, visceral metastases...
March 2018: Seminars in Diagnostic Pathology
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