Rezumat Tesutul osos reprezinta un micromediu hypoxic capabil sa potenteze metastazele tumorale si cresterea acestora.
Aceasta lucrare este o trecere in revista a datelor din literatura privind mecanismele moleculare ale hipoxiei ca unul dintre contributorii majori ai metastazelor tumorale osoase, care regleaza produsii de secretie cu rol in influentarea proliferarii si a raspandirii celulelor tumorale. Cuvinte-cheie: hypoxia, remodelarea osoasa, metastaze tumorale Abstract Bone tissue is a hypoxic microenvironment capable of potentiating tumor metastasis and growth.
Practica medicala – Revista Galenus
This gastric cancer weekly paclitaxel is a review of literature data on molecular mechanisms of hypoxia as one of the major contributors to tumor bone metastasis, regulating secreted products that drive tumor-cell proliferation and spread. Keywords:hypoxia, bone remodeling,tumor metastasis Introduction Solid tumors are particularly susceptible to hypoxia because they proliferate rapidly, outgrowing the malformed tumor vasculature, which is unable to meet the increasing metabolic demands of the expanding tumor.
Hypoxia also contributes to resistance to radiation and chemotherapy in primary tumors; it regulates normal marrow hematopoiesis and chondrocyte differentiation.
Cancer cells capable of surviving at low oxygen levels can thrive in the hypoxic bone microenvironment and participate in the vicious cycle of bone metastasis. Hypoxic signaling is mediated by hypoxia-inducible factor-1 HIF -1; ref.
С годами она приобрела гибкость и грацию. У нее была высокая стройная фигура с пышной грудью и по-юношески плоским животом.
HIF-1a expression is regulated in response to oxygen levels, whereas HIF-1h is constitutively expressed. Under normoxic conditions, oxygen-dependent prolyl hydroxylases modify HIF-1a at specific residues within the oxygen-dependent degradation domain. Hydroxylated HIF-1a is recognized and targeted for proteosomal degradation by the von Hippel-Lindau tumor suppressor, which is a component of an E ubiquitin-protein ligase 3. When oxygen levels are low,HIF-1a is no longer targeted for degradation by prolyl hydroxylases and instead, heterodimerizes with HIF-1h.
The HIF-1heterodimer enters the nucleus where it binds to hypoxia-response elements in DNA and mediates the transcription of numerous hypoxia-response genes. Hypoxic signaling is increased in cancer cells exposed to low oxygen levels in the primary tumor.
Hypoxia-response genes regulated by HIF-1 include glycolytic enzymes, glucose transporters, and vascular endothelial growth factor, which is important for angiogenesis. Many are also prometastatic, suggesting a role for hypoxia signaling in the vicious cycle of bone metastasis.
HIF-1a overexpression was correlated with advanced tumor stage rectal cancer regional lymph nodessuggesting that increased HIF-1a is associated with a more aggressive and metastatic tumor phenotype.
In vitro, HIF-1a overexpression correlated with increased invasive potential of human prostate cancer cells, as well as enhanced expression of vimentin, cathepsin D, and MMP-2,which are important for cell migration and invasion, and decreased levels of E-cadherin, which is responsible for maintenance of gastric cancer weekly paclitaxel contacts and adhesion 7.
Compendiu Volumul 1
Vimentin and E-cadherin are involved in epithelial-mesenchymal transition early in metastastic progression. Through upregulation of these proteins, HIF-1alters the phenotype of tumor cells to increase their metastatic capability.
HIF-1a increases the transcription of factors that could accelerate the vicious cycle of skeletal metastases. MET, a receptor tyrosine kinase that binds hepatocyte growth factor, is overexpressed gastric cancer weekly paclitaxel advanced breast cancer and is associated with invasion and metastasis.
HIF-1a and MET cover expression in primary tumor samples from breast cancer patients who had undergone modified radical gastric cancer weekly paclitaxel was independently correlated with metastasis and decreased year disease-free survival 8.
Traducere "anticancer" în română
HIF-1 also regulates the expression of other factors, including adrenomedullin, chemokine receptor 4, and connective tissue growth factor, with known roles in carcinogenesis and tumor metastasis 9, Expression of these factors by tumor cells is associated with enhanced proliferation and tumor spread.
Hypoxia and growth factor signaling pathways may synergistically promote the vicious cycle of skeletal metastasis. Several studies have shown crosstalk between hypoxia and growth factor signaling pathways. In normoxic conditions, the EGF receptor EGFR signaling pathway activates HIF-1a—mediated transcription of survivin, a protein which increases apoptotic resistance of human breast cancer cells, thus contributing to a more aggressive cancer phenotype As discussed previously, TGF-h is important in osteolytic bone metastases, and these results show that Gastric cancer weekly paclitaxel gastric cancer weekly paclitaxel HIF-1signaling within the hypoxic bone microenvironment.
As a regulator of tumor progression and metastasis, the hypoxia signaling pathway is an important chemotherapeutic target.
Inhibiting this pathway may prevent the development of HIF-mediated resistance to chemotherapy and radiation therapy. A number of small molecule inhibitors of hypoxia signaling are under development.
Gastric Cancer Debate: Should Radiotherapy Be Included as Part of Adjuvant Therapy? - No
One such inhibitor is 2-methoxyestradiol, a poorly estrogenic estrogen metabolite and microtubule-depolymerizing agent with antiangiogenic and antitumorigenic properties Other small molecule antihypoxic agents include inhibitors of topoisomerase I and II, such as camptothecin and GL,and inhibitors of phosphatidylinositolkinase, such as LY — all of which have been gastric cancer weekly paclitaxel to inhibit HIF mediated gene transcription Because HIF-1crosstalks with multiple signaling pathways, inhibiting hypoxia signaling alone may be inadequate to halt tumor growth and spread However, small molecule inhibitors could be useful in combination with other therapies to halt the vicious cycle of metastasis.
Acidic pH Acidosis of the bone microenvironment also potentiates the vicious cycle of bone metastasis.
Extracellular pH is tightly regulated within bone and has significant effects on osteoblast and osteoclast function. Osteoblast mineralization and bone formation is significantly impaired by acid The combined gastric cancer weekly paclitaxel on osteoclasts and osteoblasts is the release of alkaline bone mineral from the skeleton, compensating for systemic acidosis. Tumor metastasis leads to localized regions of acidosis within the skeleton Increased glycolysis and lactic acid production by proliferating cancer cells and decreased buffering capacity of the interstitial fluid contribute to the acidic microenvironment within primary tumors The acid-mediated tumor invasion hypothesis states that altered glucose metabolism in cancer cells stimulates cancer cell proliferation and results in a more invasive tumor phenotype Acidosis alters cellular dynamics at the interface between the tumor and normal tissue, promoting apoptosis in adjacent normal cells and facilitating extracellular matrix degradation through the gastric cancer weekly paclitaxel of proteolytic enzymes.
Unlike normal cells, cancer cells have compensatory mechanisms to allow proliferation and metastasis even at low extracellular pH and thus are not susceptible to acid-induced apoptosis.
Hypoxia further promotes acidosis within tumor cells through HIF-mediated overexpression of glycolytic enzymes and increased lactic acid production Together, hypoxia and pH regulatory mechanisms control survival and proliferation of tumor cells.
Tumor acidosis promotes the release and activation of proteins, such as cathepsins B, D, and L and MMPs, which degrade the gastric cancer weekly paclitaxel matrix and facilitate metastasis Cathepsin B is a cysteine proteases expressed by tumor cells, which is activated in an acidic microenvironment and could papilloma intraductal breast in the vicious cycle of bone metastasis It is expressed at low levels in primary prostate tumors; however, bone metastatic lesions express high levels of activated cathepsin B, suggesting that protease gastric cancer weekly paclitaxel is modulated by interactions between tumor cells and the bone microenvironment Hypoxia-mediated acidosis also activates numerous stress signaling cascades within tumor cells, including the nuclear factor-nB and activator protein-1pathways, which in turn regulate the transcription of prometastatic factors, such as IL-8, a cytokine important for cell motility, proliferation, and angiogenesis IL-8 expression is induced by prolonged hypoxia and decreased intracellular pH in pancreatic and prostate cancer cells Its overexpression correlates with increasing tumor grade and metastasis in many cancers, including breast and prostate.
Стратмор не имел представления о том, сколько времени прошло после ухода Сьюзан. Он сидел один в полутьме, и гул «ТРАНСТЕКСТА» звучал в его ушах.
Вы всегда добиваетесь своего… вы добьетесь… «Да, - подумал. - Я добиваюсь своих целей, но честь для меня важнее. Я скорее предпочту умереть, чем жить в тени позора».
Both hypoxia and acidosis have been implicated in schistosomiasis jaundice of cancer cells to radiation and chemotherapy.
Extracellular acidity contributes to chemotherapeutic resistance via a pH gradient that prevents the intracellular accumulation of weakly basic drugs, such as Adriamycin Conclusion The bone microenvironment contains numerous physical factors, such as hypoxia, acidosis, and extracellular calcium, and growth factors, like TGF-h, which have been implicated in this vicious cycle. These factors activate signaling pathways in cancer cells, promoting a more aggressive tumor phenotype.
Tumor acidosis is a direct consequence of hypoxia exposure. Thus, therapeutic approaches, which target hypoxia signaling may exert their beneficial effects by correcting pH in cancer cells, making them more susceptible to conventional radiation and chemotherapy. References 1.
Tyverb is used in combination with capecitabine another anticancer medicine. Tyverb este folosit în asociere cu capecitabina alt medicament împotriva cancerului. Docetaxel Winthrop is an anticancer medicine. Docetaxel Winthrop este un medicament împotriva cancerului.
Role of the hypoxic bone marrow microenvironment in 5T2MM murine myeloma tumor progression. Haematologica ;—7.