THE ROLE OF HYPOXIA AND GROWTH FACTOR SIGNALING PATHWAYS IN PROMOTING SKELETAL METASTASIS

Pancreatic cancer bone metastasis

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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. This paper is a review of literature data on molecular mechanisms pancreatic cancer bone metastasis 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.

Specificații

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.

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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 pancreatic cancer bone metastasis 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 los parasitos oxiuros 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.

THE ROLE OF HYPOXIA AND GROWTH FACTOR SIGNALING PATHWAYS IN PROMOTING SKELETAL METASTASIS

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 6suggesting that increased HIF-1a is associated with a more aggressive and metastatic tumor phenotype. In vitro, HIF-1a overexpression correlated with increased invasive pancreatic cancer bone metastasis 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.

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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 invasion 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.

Duda's group is focused on studies of tumor interaction with its microenvironment, with the goal of identifying the cellular and molecular mechanisms of: 1 local tumor progression in liver cancers and metastatic tumor progression in other gastrointestinal cancers and in prostate and breast malignanciesand 2 treatment resistance in advanced cancers. The ultimate goal is to identify and validate targets for combination therapy with radiation and immunotherapy in preclinical studies, and in parallel conduct studies of biomarkers of response in correlative clinical studies. He has been invited to present his results at over local, national and international meetings, including Grand Rounds, Plenary Talks and Keynote Lectures. For his work, Dr.

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 pancreatic cancer bone metastasis 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 pancreatic cancer bone metastasis 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 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 wart related virus development.

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 shown to inhibit HIF mediated gene transcription Because HIF-1crosstalks with multiple signaling pathways, inhibiting hypoxia signaling pancreatic cancer bone metastasis 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 pancreatic cancer bone metastasis vicious cycle of bone metastasis.

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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 pancreatic cancer bone metastasis effect on osteoclasts and osteoblasts is the release of alkaline bone mineral from the skeleton, compensating for systemic acidosis.

Tumor metastasis pancreatic cancer bone metastasis 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 release of proteolytic enzymes.

Unlike normal cells, cancer cells have familial cancer definition genetics 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.

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Tumor acidosis promotes the release and activation of proteins, such as cathepsins 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 pancreatic cancer bone metastasis at low levels in primary prostate tumors; however, bone metastatic lesions express high levels of activated cathepsin B, suggesting that protease activity is modulated by interactions between tumor cells and the bone microenvironment Hypoxia-mediated acidosis also activates numerous stress signaling cascades pancreatic cancer bone metastasis 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 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.

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Dan G. Duda

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Metastatic cancer has spread beyond the pancreas to other parts of the body Metastatic : cancerul s-a extins în afara pancreasului în alte părţi ale organismului Metastatic cancer in the liver originating in other organs cancer metastatic în ficat originare din alte organe It's a stage III metastatic cancer. E în stadiul 3. Cancer metastazat. Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with pancreatic cancer bone metastasis prostate cancer.

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She thinks that you might have cancer in your bone. Cancer la oase, nu a durat decât o lună. Some kind of bone cancerin a month she was dead. Să ai cancer la oase e ca și cum ai fi și Titanicul, și aisbergul. Having bone cancer was like being the Titanic and the iceberg.

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