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505522 occurrences (No.25 in the rank) during 5 years in the PubMed. [cache]
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505522 occurrences (No.25 in the rank) during 5 years in the PubMed. [cache]
| 116) Furthermore, mesenchymal stem cells (MSCs) and cancer-associated fibroblasts (CAFs) express high PEAK1 protein levels and potentiate tumorigenesis, lapatinib resistance and metastasis of HER2-positive breast cancer cells in a PEAK1-dependent manner. |
| PMID:34239043 DOI:10.1038/s41388-021-01906-2 |
| 2021 Oncogene |
| * A SNAI2-PEAK1-INHBA stromal axis drives progression and lapatinib resistance in HER2-positive breast cancer by supporting subpopulations of tumor cells positive for antiapoptotic and stress signaling markers. |
| - Intercellular mechanisms by which the stromal microenvironment contributes to solid tumor progression and targeted therapy resistance remain poorly understood, presenting significant clinical hurdles. PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is an actin cytoskeleton- and focal adhesion-associated pseudokinase that promotes cell state plasticity and cancer metastasis by mediating growth factor-integrin signaling crosstalk. Here, we determined that stromal PEAK1 expression predicts poor outcomes in HER2-positive breast cancers high in SNAI2 expression and enriched for MSC content. Specifically, we identified that the fibroblastic stroma in HER2-positive breast cancer patient tissue stains positive for both nuclear SNAI2 and cytoplasmic PEAK1. Furthermore, mesenchymal stem cells (MSCs) and cancer-associated fibroblasts (CAFs) express high PEAK1 protein levels and potentiate tumorigenesis, lapatinib resistance and metastasis of HER2-positive breast cancer cells in a PEAK1-dependent manner. Analysis of PEAK1-dependent secreted factors from MSCs revealed INHBA/activin-A as a necessary factor in the conditioned media of PEAK1-expressing MSCs that promotes lapatinib resistance. Single-cell CycIF analysis of MSC-breast cancer cell co-cultures identified enrichment of p-Akthigh/p-gH2AXlow, MCL1high/p-gH2AXlow and GRP78high/VIMhigh breast cancer cell subpopulations by the presence of PEAK1-expressing MSCs and lapatinib treatment. Bioinformatic analyses on a PEAK1-centric stroma-tumor cell gene set and follow-up immunostaining of co-cultures predict targeting antiapoptotic and stress pathways as a means to improve targeted therapy responses and patient outcomes in HER2-positive breast cancer and other stroma-rich malignancies. These data provide the first evidence that PEAK1 promotes tumorigenic phenotypes through a previously unrecognized SNAI2-PEAK1-INHBA stromal cell axis. |
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| (1)56 *null* | (18)5  elimination |
(35)3 that |
(52)2 does |
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(19)5 types |
(36)3 through |
(53)2 genes |
| (3)25 patients |
(20)4 disparities |
(37)3 who |
(54)2 growth |
| (4)21 cells |
(21)4 treatments |
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(55)2 incidence |
| (5)13 is |
(22)3 (CRC) |
(39)2 (2) |
(56)2 information |
| (6)12 survivors |
(23)3 (HGSOC) |
(40)2 (BC) |
(57)2 medications |
| (7)12 treatment |
(24)3 (SCLC) |
(41)2 (LC) |
(58)2 mental |
| (8)10 pain |
(25)3 SBRT |
(42)2 (NSCLC) |
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| (9)10 therapy |
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(43)2 (TNBC) |
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(27)3 diagnosis |
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(30)3 immunotherapy |
(47)2 biomarker |
(64)2 subtype-specific |
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| (15)6 cachexia |
(32)3 patient |
(49)2 cardiovascular |
(66)2 throughout |
| (16)6 care |
(33)3 patients, |
(50)2 continuum, |
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| (17)6 prevention |
(34)3 research |
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--- WordNet output for cancer ---