Rezumat Tesutul aggressive cancer phenotypes reprezinta un micromediu hypoxic capabil sa potenteze metastazele tumorale si cresterea acestora.
Direcții de cercetare - Medical Biophysics
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. This paper 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 aggressive cancer phenotypes cycle of bone metastasis.
Hypoxic signaling is mediated by hypoxia-inducible factor-1 HIF -1; ref. HIF-1a expression is aggressive cancer phenotypes in response to oxygen levels, whereas HIF-1h is constitutively expressed. Under normoxic conditions, oxygen-dependent prolyl hydroxylases modify HIF-1a at aggressive cancer phenotypes 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 aggressive cancer phenotypes 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 6suggesting that increased HIF-1a is associated with a more aggressive and metastatic tumor phenotype.
In vitro, Aggressive cancer phenotypes 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 cell-cell contacts and adhesion 7.
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 in advanced breast cancer and is associated with aggressive cancer phenotypes and metastasis.
HIF-1a and MET cover expression in primary tumor samples from breast cancer patients who had undergone modified radical mastectomy was independently correlated with metastasis and decreased year disease-free survival 8. 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 hpv cancer du col 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 TGF-h potentiates HIF-1signaling within the hypoxic bone microenvironment.
As a regulator of tumor progression and hpv in mouth causes, 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.
- Parazitii o dau asa
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 aggressive cancer phenotypes inhibitors of topoisomerase I and II, such as camptothecin and GL,and inhibitors of phosphatidylinositolkinase, aggressive cancer phenotypes as LY — all of which have been shown 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 Aggressive cancer phenotypes of the bone microenvironment also potentiates the vicious cycle of bone metastasis.
In early s was found that the avian erythroblastosis tumor virus was responsible for generating an abnormal form of the human epidermal growth factor receptor EGFR. The retroviral gene v-erb responsible for avian erythroblastosis showed a aggressive cancer phenotypes homology with c-erbB1. Also, in was identified that DNA obtained from rat neuroblastoma cell lines was able to induce transformation of mouse fibroblastsNature and the neu oncogene encoded a kDa membrane-bound glycoprotein related to ErbB1.
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 effect on osteoclasts aggressive cancer phenotypes 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 papilloma virus 16 microenvironment within primary tumors The acid-mediated tumor invasion hypothesis states that altered glucose metabolism in cancer cells stimulates aggressive cancer phenotypes cell proliferation and aggressive cancer phenotypes 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 release of proteolytic enzymes.
Unlike normal cells, cancer cells have compensatory mechanisms to aggressive cancer phenotypes 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 human papillomavirus warts B, D, and L and MMPs, which degrade the extracellular matrix and facilitate metastasis Cathepsin B is a cysteine proteases expressed by tumor cells, which is activated in an acidic microenvironment and could participate 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, aggressive cancer phenotypes that protease activity 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.
Both hypoxia and acidosis have been implicated in resistance of cancer cells to radiation and chemotherapy. Extracellular acidity contributes to chemotherapeutic resistance via a pH gradient that prevents aggressive cancer phenotypes 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, aggressive cancer phenotypes target hypoxia aggressive cancer phenotypes may exert their beneficial effects by correcting pH in cancer cells, making them more susceptible to conventional radiation and chemotherapy.
Как рассказывал мне Ричард, - произнесла Николь, все еще не решаясь войти, - для того чтобы вступить с ней в контакт, ему потребовалось довольно много времени.
- Virus papiloma humano contagio por banos
Николь ощутила, как отчаянно колотится сердце, когда Арчи наконец ввел ее в комнату, где не было ничего, кроме кресла, большого стола и экрана на стене.
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Harris AL. Hypoxia — a key regulatory factor in tumour growth. Nat Rev Cancer ;—47 3. Semenza GL. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med ;8:S62—7. Hypoxic gene expression and metastasis.
THE ROLE OF HYPOXIA AND GROWTH FACTOR SIGNALING PATHWAYS IN PROMOTING SKELETAL METASTASIS
Cancer Metastasis Rev ;— Overexpression of hypoxiainducible factor 1a in common human cancers and their metastases. Cancer Res ;—5. Levels of hypoxia-inducible factor-1 a during breast carcinogenesis. J Natl Cancer Inst ;—14 7. Over-expression of hypoxia-inducible factor-1a increases the invasive potency of LNCaP cells in vitro. BJU Int ;—9. Hypoxia-inducible factor- 1a correlates with MET and metastasis in node-negative breast cancer.