Q58035623
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- MeSH
- ATM protein genetika metabolismus MeSH
- buněčný cyklus genetika MeSH
- chronická lymfatická leukemie genetika metabolismus MeSH
- dospělí MeSH
- down regulace * MeSH
- inhibitor p27 cyklin-dependentní kinasy genetika metabolismus MeSH
- lidé MeSH
- mutace MeSH
- nádorový supresorový protein p53 genetika metabolismus MeSH
- poškození DNA * MeSH
- průtoková cytometrie MeSH
- senioři MeSH
- signální transdukce genetika MeSH
- western blotting MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- senioři MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
BACKGROUND: Small leucine rich proteoglycans (SLRPs), major non-collagen components of the extracellular matrix (ECM), have multiple biological roles with diverse effects. Asporin, a member of the SLRPs class I, competes with other molecules in binding to collagen and affects its mineralization. Its role in cancer is only now being elucidated. METHODS: The PubMed online database was used to search relevant reviews and original articles. Furthermore, altered asporin expression was analysed in publicly available genome-wide expression data at the Gene Expression Omnibus database. RESULTS: Polymorphisms in the N-terminal polyaspartate domain, which binds calcium, are associated with osteoarthritis and prostate cancer. Asporin also promotes the progression of scirrhous gastric cancer where it is required for coordinated invasion by cancer associated fibroblasts and cancer cells. Besides the enhanced expression of asporin observed in multiple cancer types, such as breast, prostate, gastric, pancreas and colon cancer, tumour suppressive effects of asporin were described in triple-negative breast cancer. We also discuss a number of factors modulating asporin expression in different cell types relevant for alterations toing the tumour microenvironment. CONCLUSION: The apparent contradicting tumour promoting and suppressive effects of asporin require further investigation. Deciphering the role of asporin and other SLRPs in tumour-stroma interactions is needed for a better understanding of cancer progression and potentially also for novel tumour microenvironment based therapies.
- MeSH
- extracelulární matrix - proteiny genetika metabolismus fyziologie MeSH
- lidé MeSH
- mikro RNA fyziologie MeSH
- nádorové mikroprostředí genetika fyziologie MeSH
- nádory etiologie genetika MeSH
- polymorfismus genetický genetika MeSH
- progrese nemoci MeSH
- tuková tkáň fyziologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Tumors are not merely masses of neoplastic cells but complex tissues composed of cellular and noncellular elements. This review provides recent data on the main components of a dynamic system, such as carcinoma associated fibroblasts that change the extracellular matrix (ECM) topology, induce stemness and promote metastasis-initiating cells. Altered production and characteristics of collagen, hyaluronan and other ECM proteins induce increased matrix stiffness. Stiffness along with tumor growth-induced solid stress and increased interstitial fluid pressure contribute to tumor progression and therapy resistance. Second, the role of immune cells, cytokines and chemokines is outlined. We discuss other noncellular characteristics of the tumor microenvironment such as hypoxia and extracellular pH in relation to neoangiogenesis. Overall, full understanding of the events driving the interactions between tumor cells and their environment is of crucial importance in overcoming treatment resistance and improving patient outcome.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity of BRCA1- or BRCA2-defective tumors (hence defective in DNA repair by homologous recombination, HR) to inhibitors of the poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme critical for repair pathways alternative to HR. While promising, treatment with PARP-1 inhibitors (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search for other sensitizing, non-BRCA1/2 cancer defects and (3) lack of biomarkers to predict response to PARP-1i. Here we addressed these issues using PARP-1i on 20 human cell lines from carcinomas of the breast, prostate, colon, pancreas and ovary. Aberrations of the Mre11-Rad50-Nbs1 (MRN) complex sensitized cancer cells to PARP-1i, while p53 status was less predictive, even in response to PARP-1i combinations with camptothecin or ionizing radiation. Furthermore, monitoring PARsylation and Rad51 foci formation as surrogate markers for PARP activity and HR, respectively, supported their candidacy for biomarkers of PARP-1i responses. As to resistance mechanisms, we confirmed the role of the multidrug resistance efflux transporters and its reversibility. More importantly, we demonstrated that shRNA lentivirus-mediated depletion of 53BP1 in human BRCA1-mutant breast cancer cells increased their resistance to PARP-1i. Given the preferential loss of 53BP1 in BRCA-defective and triple-negative breast carcinomas, our findings warrant assessment of 53BP1 among candidate predictive biomarkers of response to PARPi. Overall, this study helps characterize genetic and functional determinants of cellular responses to PARP-1i and contributes to the search for biomarkers to exploit PARP inhibitors in cancer therapy.
- MeSH
- chemorezistence * MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- enzymy opravy DNA genetika metabolismus MeSH
- geny MDR MeSH
- inhibitory enzymů farmakologie MeSH
- intracelulární signální peptidy a proteiny * genetika MeSH
- kamptothecin farmakologie MeSH
- karcinom * farmakoterapie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- poškození DNA MeSH
- protein BRCA1 genetika metabolismus MeSH
- protein BRCA2 genetika MeSH
- proteiny buněčného cyklu genetika metabolismus MeSH
- protinádorové látky farmakologie MeSH
- regulace genové exprese u nádorů * MeSH
- záření gama terapeutické užití MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
Background. The Wnt signaling pathway is crucial for cell fate decisions, stem cell renewal, regulation of cell proliferation and differentiation. Deregulated Wnt signaling is also implicated in a number of hereditary and degenerative diseases and cancer. Methods and results. This review highlights the role of the Wnt pathway in the regulation of stem/progenitor cell renewal and prostate gland development and how this signaling is altered in prostate cancer. Recent evidence suggests that Wnt signaling regulates androgen activity in prostate cancer cells, enhances androgen receptor expression and promotes the growth of prostate cancer even after androgen ablation therapy. There is also strong evidence that Wnt signaling is enhanced in androgen-ablation resistant tumors and bone metastases. Conclusions. Further study of the modulators of this pathway will be of therapeutic relevance as inhibition of Wnt signaling may have the potential to reduce the self-renewal and aggressive behaviour of prostate cancer while Wnt signaling activation might enhance stem cell activity when tissue regeneration is required.
