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Polycythemia vera (PV) is a clonal disorder resulting from neoplastic transformation of hematopoietic stem cells, while secondary polycythemia (SP) is a disease characterized by increased absolute red blood cell mass caused by stimulation of red blood cell production. Although the physiopathology of SP and PV is distinct, patients with these diseases share similar symptoms. The early differential diagnosis may improve the quality of life and decrease the disease burden in PV patients, as well as enable curative treatment for SP patients. PV is considered an oncoinflammatory disease because PV patients exhibit augmented levels of several pro-inflammatory cytokines. In this sense, we examined whether analysis of the cytokine production profile of SP and PV patients would help to distinguish them, despite their clinical similarities. Here we reported that SP patients exhibited decreased plasma levels of, IL-17A, IFN-γ, IL-12p70 and TNF-α when compared with PV patients, suggesting that analysis of the cytokine production profile may be an useful diagnostic biomarker to distinguish PV from SP patients. Polycythemia vera (PV) and secondary polycythemia (SP) are hematological diseases characterized by erythropoiesis exacerbation. PV patients present clonal expansion of the hematopoietic erythroid progenitor and, to a lesser extent, leukocytosis and/or thrombocytosis 1. PV affects more women than men, has an incidence of 0.68-2.6 for every 100,000 individuals per year, and is uncommon in patients younger than 60 years. PV patients have life expectancy of 14 years after diagnosis, and their major risk factors for mortality are thrombotic events and leukemic transformation 2,3. The augmented levels of pro-inflammatory cytokines in PV patients give this neoplasm the status of oncoinflammatory disease 4-6. Secondary polycythemia (SP) is a poorly understood clinical entity. The SP prevalence is considerably high, but it is hard to quantify due to the variety of causes and scarcity of data 7. Compared with PV patients, SP patients have lower overall survival 8,9 and higher morbidity and mortality rates, as demonstrated by small non-randomized studies. In spite of the epidemiological evidence, it is not clear whether the high mortality rate is associated with the increased red blood cell volume. To date, no randomized studies were conducted to analyze whether the morbidity and/or mortality rates in SP patients correlate with the increased red blood cell volume and thrombosis 7. SP can be congenital, caused by erythropoietin (EPO) receptor mutations, or acquired and induced by physiological changes that raise the body demand for oxygen, such as renal, lung and heart disease, high altitudes, severe obesity, defective oxygen transport, and EPO overproduction caused by certain kidney diseases or secretion by some tumors 8-10. The increment in erythrocyte mass in SP patients results from bone marrow stimulation by EPO or abnormal functioning of the mutant EPO receptor. In contrast to PV patients, SP patients do not have increased le...
Polycythemia vera (PV) is a clonal disorder resulting from neoplastic transformation of hematopoietic stem cells, while secondary polycythemia (SP) is a disease characterized by increased absolute red blood cell mass caused by stimulation of red blood cell production. Although the physiopathology of SP and PV is distinct, patients with these diseases share similar symptoms. The early differential diagnosis may improve the quality of life and decrease the disease burden in PV patients, as well as enable curative treatment for SP patients. PV is considered an oncoinflammatory disease because PV patients exhibit augmented levels of several pro-inflammatory cytokines. In this sense, we examined whether analysis of the cytokine production profile of SP and PV patients would help to distinguish them, despite their clinical similarities. Here we reported that SP patients exhibited decreased plasma levels of, IL-17A, IFN-γ, IL-12p70 and TNF-α when compared with PV patients, suggesting that analysis of the cytokine production profile may be an useful diagnostic biomarker to distinguish PV from SP patients. Polycythemia vera (PV) and secondary polycythemia (SP) are hematological diseases characterized by erythropoiesis exacerbation. PV patients present clonal expansion of the hematopoietic erythroid progenitor and, to a lesser extent, leukocytosis and/or thrombocytosis 1. PV affects more women than men, has an incidence of 0.68-2.6 for every 100,000 individuals per year, and is uncommon in patients younger than 60 years. PV patients have life expectancy of 14 years after diagnosis, and their major risk factors for mortality are thrombotic events and leukemic transformation 2,3. The augmented levels of pro-inflammatory cytokines in PV patients give this neoplasm the status of oncoinflammatory disease 4-6. Secondary polycythemia (SP) is a poorly understood clinical entity. The SP prevalence is considerably high, but it is hard to quantify due to the variety of causes and scarcity of data 7. Compared with PV patients, SP patients have lower overall survival 8,9 and higher morbidity and mortality rates, as demonstrated by small non-randomized studies. In spite of the epidemiological evidence, it is not clear whether the high mortality rate is associated with the increased red blood cell volume. To date, no randomized studies were conducted to analyze whether the morbidity and/or mortality rates in SP patients correlate with the increased red blood cell volume and thrombosis 7. SP can be congenital, caused by erythropoietin (EPO) receptor mutations, or acquired and induced by physiological changes that raise the body demand for oxygen, such as renal, lung and heart disease, high altitudes, severe obesity, defective oxygen transport, and EPO overproduction caused by certain kidney diseases or secretion by some tumors 8-10. The increment in erythrocyte mass in SP patients results from bone marrow stimulation by EPO or abnormal functioning of the mutant EPO receptor. In contrast to PV patients, SP patients do not have increased le...
The recombinant growth factors (GFs) erythropoietin (Epo) and granulocyte-macrophage colony stimulating factor (GM-CSF) have important roles in the management of cancer patients. However, the effects of these GFs at a cellular level are not well understood. We examined the effect of GFs alone, and in combination with cytotoxic chemotherapy, in a panel of seven cell lines. Flow cytometric analysis showed varying levels of receptor expression, which correlated with phosphorylated MAPK expression. Additionally, there were also concomitant increases in BCL-2 protein levels in those cells with high levels of MAPK activation. Although culturing cells with Epo or GM-CSF did not alter cell viability by themselves, GF pretreatment in cell lines expressing higher receptor levels resulted in a reduced magnitude of cell kill following exposure to cytotoxic IC 50 concentrations of cisplatin. Subsequent co-culture with either the MEK inhibitor U0126 or the GM-CSF antagonist E21R negated this induced resistance to cytotoxic chemotherapy, confirming the importance of the GF receptor as well as MAPK in mediating these effects. These results suggest that the use of GFs during chemotherapy may be detrimental in those cancers expressing higher levels of the specific receptor. Conversely, our results also suggest that GFs are safe to use in chemotherapeutic regimens if the cancer cells do not overexpress the particular receptor.
Germ line mutations in the VHL tumor suppressor gene result in von Hippel-Lindau (VHL) disease, a familial tumor syndrome that predisposes affected patients to the development of highly vascularized neoplasms. These include hemangioblastomas of the retina and central nervous system (CNS), renal-cell carcinomas (RCC) of the clear-cell type, and endocrine and exocrine pancreatic tumors, as well as pheochromocytomas (34). In addition, VHL has also been found to be inactivated in the majority of sporadic RCC (8, 13).VHL deficiency leads to constitutive activation of hypoxiainducible factor (HIF) and increased expression of its target genes irrespective of the oxygen concentration (38). The VHL gene product (pVHL), together with elongins B and C (6, 25), Cullin-2 (43), and Rbx1 (23), forms an E3 ubiquitin ligase (19), which targets the hydroxylated, oxygen-sensitive ␣ subunits of HIF-1, -2, and -3 for ubiquitination and subsequent degradation by the 26S proteasome (18,20,39). As a normal physiological response to hypoxia, HIF-1 and HIF-2 facilitate both oxygen delivery and adaptation to oxygen deprivation by regulating genes that are involved in glucose uptake and metabolism, angiogenesis, erythropoiesis, cell proliferation, and apoptosis (50, 62). HIFs belong to the PAS (Per-Arnt-Sim) family of basic helix-loop-helix (bHLH) transcription factors that bind to DNA as heterodimers composed of an oxygensensitive ␣ subunit and a constitutively expressed  subunit, also known as the arylhydrocarbon receptor nuclear translocator (ARNT). ARNT is the general binding partner for the bHLH/PAS domain-containing proteins. In addition to forming heterocomplexes with HIF, ARNT also heterodimerizes with single minded (SIM), which is involved in neural development, and with the arylhydrocarbon receptor (AhR), which is involved in the xenobiotic response to environmental toxins (for a review, see reference 24).The expression patterns of the HIF subunits differ within embryonic and adult tissues. In the adult, Hif-1␣ mRNA is ubiquitously expressed, and Hif-1␣ protein can be detected at baseline levels within multiple cell types in various tissues under normoxia and is significantly enhanced under conditions of hypoxia (55). In contrast, while Hif-2␣ mRNA expression has been detected within many tissues, Hif-2␣ protein has been found to be restricted to specific cell types within various tissues. In addition to being expressed in endothelial cells, Hif-2␣ is also expressed in glial cells of the brain, type II pneumocytes of the lung, cardiomyocytes, fibroblasts of the kidney, intersitial cells of the pancreas and duodenum, and hepatocytes (26,63). Arnt expression is ubiquitous, and it seems to be the only Hif- subunit present in the liver (21).pVHL appears to have multiple functions besides regulating HIF, and its contributions to the development of VHL-associated tumors are presently subject to intense investigations. As a result of these efforts, it has been shown that pVHL plays an important role in fibronectin extracellular-matrix...
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