دورية أكاديمية
أعرض في EDS

Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.

التفاصيل البيبلوغرافية
العنوان: Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.
المؤلفون: Murali B; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri., Ren Q; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri., Luo X; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri., Faget DV; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri., Wang C; Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri., Johnson RM; Goodman Cancer Center, Department of Oncology, Department of Biochemistry, McGill University, Montreal, Quebec, Canada., Gruosso T; Goodman Cancer Center, Department of Oncology, Department of Biochemistry, McGill University, Montreal, Quebec, Canada., Flanagan KC; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri., Fu Y; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri., Leahy K; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri., Alspach E; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri., Su X; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Ross MH; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Burnette B; Aclaris Therapeutics, Inc., Saint Louis, Missouri., Weilbaecher KN; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Park M; Goodman Cancer Center, Department of Oncology, Department of Biochemistry, McGill University, Montreal, Quebec, Canada., Mbalaviele G; Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri., Monahan JB; Aclaris Therapeutics, Inc., Saint Louis, Missouri., Stewart SA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri. sheila.stewart@wustl.edu.; Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.; ICCE Institute, Washington University School of Medicine, St. Louis, Missouri.
المصدر: Cancer research [Cancer Res] 2018 Oct 01; Vol. 78 (19), pp. 5618-5630. Date of Electronic Publication: 2018 Aug 09.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: Baltimore, Md. : American Association for Cancer Research
Original Publication: Chicago [etc.]
مواضيع طبية MeSH: Antineoplastic Agents/*adverse effects , Bone and Bones/*drug effects , Breast Neoplasms/*drug therapy , Breast Neoplasms/*metabolism , Intracellular Signaling Peptides and Proteins/*metabolism , Protein Serine-Threonine Kinases/*metabolism , p38 Mitogen-Activated Protein Kinases/*metabolism, Administration, Oral ; Animals ; Bone Neoplasms/secondary ; Bone and Bones/pathology ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Disease Progression ; Drug Therapy ; Female ; HEK293 Cells ; Humans ; Induction Chemotherapy ; MAP Kinase Signaling System ; Macrophages/metabolism ; Mice ; Neoplasm Metastasis ; Osteoclasts/metabolism ; Paclitaxel/pharmacology ; Prognosis ; Quality of Life ; Stromal Cells/metabolism ; Tumor Microenvironment
مستخلص: The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPKα could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase MK2 each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. This effect was primarily mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity that drastically affects quality of life for patients with cancer. These data underscore the vital role played by stromal-derived factors in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss. Significance: Pharmacologically targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth, preserves bone quality, and extends survival. Cancer Res; 78(19); 5618-30. ©2018 AACR .
(©2018 American Association for Cancer Research.)
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معلومات مُعتمدة: P50 CA094056 United States CA NCI NIH HHS; T32 CA113275 United States CA NCI NIH HHS; F31 CA189669 United States CA NCI NIH HHS; R01 AR068972 United States AR NIAMS NIH HHS; P30 CA091842 United States CA NCI NIH HHS; UL1 TR000448 United States TR NCATS NIH HHS; T32 GM007067 United States GM NIGMS NIH HHS; UL1 TR002345 United States TR NCATS NIH HHS; P01 CA100730 United States CA NCI NIH HHS; R01 CA217208 United States CA NCI NIH HHS; R01 AR064755 United States AR NIAMS NIH HHS; T32 AR060719 United States AR NIAMS NIH HHS; R24 NS086741 United States NS NINDS NIH HHS; R56 CA097250 United States CA NCI NIH HHS; R01 CA097250 United States CA NCI NIH HHS; P30 AR057235 United States AR NIAMS NIH HHS; R01 CA130919 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Intracellular Signaling Peptides and Proteins)
EC 2.7.1.- (MAP-kinase-activated kinase 2)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
P88XT4IS4D (Paclitaxel)
تواريخ الأحداث: Date Created: 20180811 Date Completed: 20191007 Latest Revision: 20240610
رمز التحديث: 20240610
مُعرف محوري في PubMed: PMC6168362
DOI: 10.1158/0008-5472.CAN-18-0234
PMID: 30093561
قاعدة البيانات: MEDLINE
الوصف
تدمد:1538-7445
DOI:10.1158/0008-5472.CAN-18-0234