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Geza Acs

Publications and source records attributed to Geza Acs.

At least 19 recordsLinked to original sources
PubMed2007

Extensive retraction artifact correlates with lymphatic invasion and nodal metastasis and predicts poor outcome in early stage breast carcinoma.

Retraction artifact resulting in clear spaces around tumor cell nests is frequently seen in histologic material and may present difficulty in their differentiation from lymphovascular invasion. We noticed that retraction artifact seemed to be more common around groups of breast cancer cells compared with benign acini, and when extensively present, metastasis to axillary lymph nodes was often seen. Thus, we performed a study of 304 cases of stage pT1 and pT2 breast carcinomas to test our hypothesis that extensive retraction artifact in tumors correlates with lymphatic spread and outcome. Tumors were evaluated to determine the presence and extent of retraction artifact around tumor cell nests and the presence of lymphatic invasion. Lymphatic invasion was confirmed by D2-40 immunostaining. The extent of retraction artifact in tumors was correlated with clinicopathologic tumor features and patient outcome. Variable degree of retraction artifact was present in 183 of 304 (60%) invasive carcinomas, with its extent ranging from 0% to 90% (median 5%). The extent of retraction artifact showed a significant correlation with tumor size, histologic type, histologic grade, presence of lymphovascular invasion, and nodal metastasis. Further, extensive retraction artifact was significantly associated with poor overall and disease-free survival in both univariate and multivariate analyses. We propose that the apparent retraction of the stroma from cells of invasive breast carcinoma on routine histologic sections is not a phenomenon merely due to inadequate fixation as currently believed. Rather, it likely signifies important biologic changes that alter tumor-stromal interactions and contribute to lymphatic spread and tumor progression.

Artifacts↗
PubMed2007

Immunoprofile of endocervical and endometrial stromal cells and its potential application in localization of tumor involvement.

To evaluate and compare the immunophenotype of endocervical and endometrial stromal cells and to asses its potential application in tumor localization. Paraffin sections of benign endocervix (n = 24), benign endometrium (n = 33), endocervical adenocarcinoma (n = 9), endometrial carcinoma (n = 13), and endometrial hyperplasia (n = 16) were stained with antibodies to CD10, Wilms Tumor-1, CD34, smooth muscle actin, and factor XIIIa by immunohistochemistry. In 16 cases, lower uterine segment was also available. Immunoreactivity of stromal cells was recorded as positive (>/=50% staining), focally positive (>/=5%-<50%) or negative (<5%). Endocervical stromal cells (ECSC) in either benign or malignant cervical epithelial lesions were predominantly CD34/CD10 (CD34 dominant immunophenotype). Endometrial stromal cells (EMSCs) in either benign or malignant epithelial lesions were primarily CD34/CD10 (CD10 dominant immunophenotype). Expression of Wilms Tumor-1 was decreased in EMSC of the EMCA when compared to their counterpart in endometrial hyperplasia. There was no differential expression of smooth muscle actin and factor XIIIa identified between ECSC and EMSC. The immunophenotypes of the ECSC and EMSC overlapped in the lower uterine segment. The functional status of the endometrium had no effect on the immunoprofile. The pattern of CD34 and CD10 immunostaining in stromal cells might be helpful in determining tumor involvement in uterine and cervical sites.

Endometrial Neoplasms↗
PubMed2006

Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation.

Lymphatic invasion and nodal metastasis are predictors of poor outcome in cervix carcinoma. We have recently found that low podoplanin immunoreactivity in cervix carcinoma correlated with the presence of lymphatic invasion and nodal metastasis. In the current study, we examined whether podoplanin expression in pretreatment cervical biopsies can predict the presence lymphatic invasion, nodal metastasis, and outcome in advanced-stage tumors treated by nonsurgical means. Podoplanin expression was analyzed by immunohistochemistry in 48 cervical biopsies and corresponding hysterectomy specimens of early-stage invasive squamous cell carcinoma and in 74 pretreatment biopsies from advanced-stage tumors treated with primary radiation. We found a highly significant correlation between podoplanin expression obtained in biopsy and corresponding hysterectomy materials (r = 0.8962, P < 0.0001). Low podoplanin expression showed a significant correlation with lymphatic invasion (P < 0.0001) and nodal metastasis (P = 0.0058). Low podoplanin expression in pretreatment biopsy material showed a significant correlation with poor disease-free (P = 0.0009) and overall (P = 0.0002) survival in advanced-stage tumors. Our results suggest that in advanced-stage cervix carcinomas treated by radiation, when traditional prognostic indicators are not available and treatment decisions are based on biopsy material and clinical staging parameters, examination of podoplanin expression in pretreatment biopsy material may be a useful marker to predict lymphatic metastasis and patient outcome. Prospective studies involving larger numbers of patients are needed to further evaluate the clinical utility of examination of podoplanin expression in patients with cervix carcinoma.

Biopsy↗
PubMed2006

Can Melan-A replace S-100 and HMB-45 in the evaluation of sentinel lymph nodes from patients with malignant melanoma?

The sentinel lymph node (SLN) biopsy has become an increasingly important procedure used in the primary staging of malignant melanoma. However, micrometastases in a lymph node can be easily missed on routine H&E-stained sections. Therefore, S-100 and HMB-45 IHC stains are standardly performed on grossly negative SLNs for detection of metastatic melanoma. Each of these IHC markers, however, is not ideal. The authors investigated whether the newer IHC marker Melan-A would improve the detection of metastatic melanoma in SLN biopsies. Forty lymph nodes previously diagnosed with metastatic melanoma were retrospectively evaluated for S-100, HMB-45, and Melan-A expression. In addition, 42 SLN biopsies for metastatic melanoma detection were prospectively collected and evaluated for S-100, HMB-45, and Melan-A expression. All lymph nodes with metastatic melanoma from the retrospective study demonstrated S-100 reactivity. Five of the lymph nodes with metastatic melanoma from the retrospective study failed to express either HMB-45 or Melan-A, all of which displayed a desmoplastic morphology. One of the metastases positive for S-100 and HMB-45 failed to show reactivity with Melan-A (3%). The prospective study found 10 lymph nodes from 42 cases to be positive for metastatic melanoma, which were positive for S-100 (100%). Nine of the involved lymph nodes were positive for HMB-45(90%), and nine were positive for Melan-A (90%). Melan-A, although very specific, cannot replace the use of S-100 and HMB-45 for the detection of metastatic melanoma in SLNs. It can, however, substitute for HMB-45 with equally good results.

Antigens, Neoplasm↗
PubMed2006

Erythropoietin activates the phosphoinositide 3-kinase/Akt pathway in human melanoma cells.

Erythropoietin (Epo) is used commonly to treat cancer and/or therapy-related anemia. Until recently, Epo was considered to be a specific stimulator of erythropoiesis, acting via its receptor, EpoR. It becomes clear, however, that EpoR is expressed in a variety of cell types other than hematopoietic cells, and that Epo is a potent cytoprotective cytokine increasing cell survival under hypoxic conditions. Epo and EpoR are also expressed in various malignant tumors, and EpoR expression shows association with tumor invasion and progression. Recently, a functional Epo autocrine signaling mechanism was also detected in human melanoma cells. In this study, we examined the hypothesis that Epo activates the Akt signaling pathway in human melanoma cells and thus promotes the survival of tumor cells. The Akt signaling pathway in response to Epo was examined in melanoma. Similar to Epo, the expression of EpoR was up-regulated in response to hypoxia and Epo stimulation in melanoma cells. Melanoma cells constitutively expressed Akt with variable expression of mammalian target of rapamycin, and Epo dose-dependently induced their activity. Epo increased Akt kinase activity, which was abrogated by co-treatment with LY294002, a specific blocker of phosphoinositide 3-kinase. LY294002 also inhibited the cytoprotective effects of Epo in melanoma cells under both normoxic and hypoxic conditions. Our results suggest that Epo promotes melanoma cell survival by activating an Akt-dependent signaling pathway.

Cell Proliferation↗
PubMed2006

Isolation of a novel population of multipotent adult stem cells from human hair follicles.

Hair follicles are known to contain a well-characterized niche for adult stem cells: the bulge, which contains epithelial and melanocytic stem cells. Using human embryonic stem cell culture conditions, we isolated a population of adult stem cells from human hair follicles that are distinctively different from known epithelial or melanocytic stem cells. These cells do not express squamous or melanocytic markers but express neural crest and neuron stem cell markers as well as the embryonic stem cell transcription factors Nanog and Oct4. These precursor cells proliferate as spheres, are capable of self-renewal, and can differentiate into multiple lineages. Differentiated cells not only acquire lineage-specific markers but also demonstrate appropriate functions in ex vivo conditions. Most of the Oct4-positive cells in human skin were located in the area highlighted by cytokeratin 15 staining in vivo. Our data suggest that human embryonic stem cell medium can be used to isolate and expand human adult stem cells. Using this method, we isolated a novel population of multipotent adult stem cells from human hair follicles, and these cells appear to be located in the bulge area. Human hair follicles may provide an accessible, autologous source of adult stem cells for therapeutic application.

Cell Culture Techniques↗
PubMed2006

Repeat operative sentinel lymph node biopsy.

Because sentinel lymph node (SLN) biopsy continues to be used for staging in patients with breast cancer, physicians treating these patients will be faced with in-breast recurrences and new primary breast cancers in the treated breast. Repeat operative SLN biopsy might be feasible in this clinical scenario. This report describes the case of a patient with an ipsilateral different-site, recurrent, infiltrating ductal carcinoma 14 months after lumpectomy; negative SLN biopsy result; and radiation therapy, now with a positive SLN biopsy result.

Breast Neoplasms↗
PubMed2005

Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix.

PURPOSE: Lymphatic invasion and nodal metastasis plays a major role in the spread of cervical cancer; however, little is known about the mechanisms whereby tumor cells enter the lymphatic system. EXPERIMENTAL DESIGN: We examined the intra- and peritumoral lymphatic vessel density (LVD) using D2-40 immunohistochemistry in 111 cervical squamous cell carcinomas and correlated them with vascular endothelial growth factor (VEGF)-C expression, clinicopathologic tumor features, and outcome. RESULTS: Compared with benign cervix, intratumoral and peritumoral LVD was significantly increased (P < 0.0001). Peritumoral LVD was significantly higher than intratumoral LVD (P = 0.009). High peritumoral, but not intratumoral, LVD showed significant correlation with high tumor stage, lymphatic invasion, and nodal metastasis. VEGF-C showed increased expression at the invasive edge compared with the center of tumors (P < 0.0001) and correlated with high peritumoral LVD, lymphatic invasion, and nodal metastasis. High peritumoral LVD and VEGF-C expression at the invasive edge of tumors were associated with poor overall and recurrence-free survival in univariate analysis. In multivariate analysis, peritumoral LVD was the only independent term predictive of overall survival. CONCLUSIONS: Our findings suggest a potential role for VEGF-C in tumor-induced lymphangiogenesis represented by high peritumoral LVD, which may be one of the mechanisms leading to lymphatic invasion and metastatic spread. High peritumoral LVD may be an independent prognostic factor in early-stage cervical cancer.

Carcinoma in Situ↗
PubMed2005

Erythropoietin receptor function and expression in epithelial ovarian carcinoma.

OBJECTIVE: Our objectives were to determine if the erythropoietin receptor (EpoR) has increased expression in epithelial ovarian carcinoma, and if erythropoietin (Epo) confers malignant properties to ovarian cancer cell lines. METHODS: A Western blot analysis of protein lysates from normal ovarian surface epithelial cells and ovarian cancer cell lines was performed. In addition, immunohistochemical (IHC) staining for EpoR in tissue specimens of normal, low malignant potential tumor, and epithelial ovarian carcinoma was performed. Epo effect on ovarian cancer cell lines was investigated by a cytotoxicity assay using a cell line with high (OVCAR3) and low (SKOV3) EpoR expression. RESULTS: Western blot analysis revealed increased expression of EpoR in multiple ovarian cancer cell lines. IHC staining revealed limited EpoR expression in benign ovarian tissue and increased levels in ovarian low malignant potential (LMP) tumor and carcinoma. This difference between benign ovarian tissue and carcinoma was found to be statistically significant using a quantitative scoring system. In addition, a cytotoxicity assay with paclitaxel and cisplatin revealed an attenuation of cytotoxic effects. CONCLUSION: Increased EpoR expression in ovarian LMP tumors and carcinoma is demonstrated by Western blot analysis and IHC staining. Furthermore, adversely effects sensitivity to cisplatin in the ovarian cancer cell lines. These data add to the growing body of evidence suggesting possible detrimental effects of erythropoietin.

Antineoplastic Agents↗
PubMed2005

Functional erythropoietin autocrine loop in melanoma.

Although erythropoietin (Epo) is a known stimulator of erythropoiesis, recent evidence suggests that its biological functions are not confined to hematopoietic cells. To elucidate the role of Epo and erythropoietin receptor (EpoR) in melanoma, we examined the expression and function of these proteins in melanocytes and melanoma cells. We found increased expression of Epo in melanoma cells compared to melanocyte in vitro. EpoR was also strongly expressed in all of the melanoma cell lines and two of the three melanocyte cell lines examined. Epo expression was significantly higher in melanoma than in benign nevi as determined by immunohistochemistry. Although melanoma cells secreted Epo in normoxic condition in vitro, hypoxia and CoCl(2) treatment increased Epo secretion. EpoR in melanoma cells was functional, because exogenous Epo increased melanoma resistance to hypoxic stress, pretreatment of melanoma cells with Epo significantly increased resistance to dacarbazine treatment, and Epo increased the phosphorylation of EpoR, RAF, and MEK. In conclusion, we demonstrated constitutive expression of Epo and EpoR as well as autonomous secretion of Epo by melanoma cells, indicating a novel autocrine loop of Epo in melanoma. The results suggest that the autocrine and paracrine functions of Epo might play a role in malignant transformation of melanocytes and in the survival of melanoma cells in hypoxia and other adverse conditions.

Blotting, Western↗
PubMed2005

Utility of D2-40, a novel mesothelial marker, in the diagnosis of malignant mesothelioma.

Although immunohistochemistry has proven to be valuable in the differentiation of epithelioid mesothelioma from pulmonary or metastatic adenocarcinoma, no single antibody has demonstrated absolute sensitivity or specificity in making this distinction. Using immunohistochemical analysis with D2-40, a recently available monoclonal antibody that has been used as a lymphatic endothelial marker, we examined 53 cases of mesothelioma, 28 cases of reactive pleura, 30 cases of pulmonary adenocarcinoma, 35 cases of renal cell carcinoma, 26 cases of ovarian serous carcinoma, 16 cases of invasive breast carcinoma, 11 cases of prostatic adenocarcinoma, and seven cases of urothelial carcinoma. In addition, immunohistochemistry using calretinin, cytokeratin 5/6, and WT1 was performed on all cases of mesothelioma, pulmonary adenocarcinoma, ovarian serous carcinoma, and renal cell carcinoma. Predominantly, membranous D2-40 immunoreactivity was present in 51 of 53 (96%) mesotheliomas, 27 of 28 (96%) cases of reactive pleura, and 17 of 26 (65%) ovarian serous carcinomas; membranous staining was not seen in any other tumors examined. Compared to other immunohistochemical markers of mesothelioma, D2-40 was as sensitive as calretinin and more sensitive than cytokeratin 5/6 and WT1. We conclude that D2-40 immunoreactivity is sensitive for cells of mesothelial origin, and may be useful in the differential diagnosis of epithelioid malignant mesothelioma vs adenocarcinoma.

Antibodies, Monoclonal↗
PubMed2005

Low D2-40 immunoreactivity correlates with lymphatic invasion and nodal metastasis in early-stage squamous cell carcinoma of the uterine cervix.

Lymphatic invasion and nodal metastasis are predictors of shorter disease-free and overall survival in carcinoma of the uterine cervix. The monoclonal antibody D2-40, which reacts with the oncofetal membrane antigen M2A, is a new selective marker for lymphatic endothelium, and has been shown to be useful in identifying the presence of lymphatic invasion in various malignant neoplasms, including cervical carcinoma. However, the reactivity of the tumor cells with D2-40 has not yet been evaluated. In this study, we examined the pattern of D2-40 immunoreactivity in a series of 138 invasive squamous cell carcinomas of the uterine cervix. We correlated the presence and extent of D2-40 immunoreactivity in the tumor cells with various clinicopathologic features, the presence of lymphatic invasion, lymph node metastasis and outcome. Diffuse or focal D2-40 immunoreactivity was present in 17 (12%) and 81 (59%) tumors, respectively, while 40 (29%) tumors showed no immunoreactivity. Lymphatic invasion and nodal metastasis were present in 56 and 29% of tumors, respectively. Tumor emboli within lymphatic spaces and metastatic tumor foci in lymph nodes showed no immunoreactivity in 86 and 80% of the cases, respectively. Lymphatic invasion and nodal metastasis were significantly more common in tumors showing low D2-40 immunoreactivity (P<0.0001 and 0.022, respectively). D2-40 immunoreactivity showed no correlation with any other clinicopathologic features examined, including tumor size, grade and FIGO stage. In univariate analysis low D2-40 immunoreactivity was significantly associated with shorter recurrence-free, but not with overall survival. Our studies suggest that D2-40 immunostaining may serve as a marker for increased risk of lymphatic invasion and tumor recurrence in cervical biopsy material. Further study of the biological function of the M2A antigen may shed some light on the interaction of tumor cells with lymphatics.

Analysis of Variance↗
PubMed2005

Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR.

A highly distinctive subset of renal neoplasms of children and young adults contains a t(6;11)(p21;q12), a translocation recently been shown to result in fusion of Alpha, a gene on 11q12, with the transcription factor gene TFEB on 6p21. To define the clinicopathologic spectrum of this nascent entity and to establish immunohistochemical (IHC) and molecular methods for the detection of the specific Alpha-TFEB fusion, we studied 7 renal neoplasms that showed the t(6;11) by cytogenetic or molecular analysis (patient age: range, 9-33 years; mean, 17 years). While all tumors were confined to the kidney, 3 tumors demonstrated vascular invasion. In limited follow-up, none has metastasized. We postulated that the Alpha-TFEB gene fusion may result in deregulated expression of TFEB protein that would be detectable by IHC. Using a polyclonal antibody to TFEB on formalin-fixed, paraffin-embedded tissue sections, we found that all 7 renal neoplasms with the t(6;11) demonstrated moderate (2 cases) or strong (5 cases) nuclear TFEB immunoreactivity. In contrast, none of 1089 other tumors (of 74 histologic types from 16 sites) labeled significantly for TFEB. Nuclear immunoreactivity for TFEB in normal tissues was extremely rare, limited to weak labeling of scattered benign lymphocytes. We also show that the Alpha-TFEB fusion RNAs are highly variable in size and structure, making detection by reverse-transcriptase polymerase chain reaction (RT-PCR) less reliable than for other gene fusions. Because Alpha is an intronless gene and therefore lacks splice signals, we hypothesized that DNA PCR and RT-PCR products would be identical, allowing for the use of more robust molecular assays based on genomic DNA. Indeed, in 2 cases with available frozen tissue, we showed the genomic Alpha-TFEB junction detected by DNA PCR to be identical to the Alpha-TFEB fusion mRNA detected by RT-PCR. In summary, renal neoplasms with the t(6;11) are a distinctive neoplastic entity with many similarities to the Xp11 translocation carcinomas, and together with the latter form a growing "MiTF/TFE family" of translocation carcinomas. Nuclear immunoreactivity for TFEB protein is a highly sensitive and specific diagnostic marker for these renal neoplasms. Finally, the special molecular features of the Alpha-TFEB gene fusion allow its molecular detection by DNA PCR as a robust alternative to RT-PCR in clinical tumor samples.

Adolescent↗
PubMed2005

Serous and mucinous borderline (low malignant potential) tumors of the ovary.

The prognosis for stage I serous borderline ovarian tumors (SBOTs) is thought to be excellent, despite rare, late recurrences. The behavior of advanced-stage SBOTs primarily depends on the invasiveness vs noninvasiveness of associated extraovarian implants. Pelvic and abdominal lymph node involvement and foci of microinvasion do not seem to adversely affect prognosis. Serous tumors with a micropapillary and/or cribriform growth pattern seem to be more frequently bilateral and exophytic and manifest at an advanced stage with a higher incidence of invasive implants than typical SBOTs. Molecular data suggest that such tumors may represent an intermediate stage in the typical SBOT-invasive low-grade serous carcinoma progression. Limited experience with endocervical (müllerian)-type mucinous borderline tumors shows a possible relation to SBOTs in clinicopathologic features and biologic behavior Intestinal-type mucinous borderline ovarian tumors (I-MBOTs) and well-differentiated mucinous carcinomas manifest at stage I in most cases; the prognosis is excellent. Mucinous tumors associated with pseudomyxoma peritonei are almost always secondary to similar tumors of the appendix or other gastrointestinal sites and should not be diagnosed as high-stage I-MBOTs. Rare primary ovarian mucinous tumors associated with pseudomyxoma peritonei are those arising in mature cystic teratomas. Advanced-stage ovarian mucinous carcinomas typically show frank, infiltrative-type invasion; the prognosis is poor.

Cystadenocarcinoma, Mucinous↗
PubMed2005

Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma.

Erythropoietin (Epo) is used for managing anemia in cancer patients. However, recent studies have raised concerns for this practice. We investigated the expression and function of Epo and the erythropoietin receptor (EpoR) in tumor biopsies and cell lines from human head and neck cancer. Epo responsiveness of the cell lines was assessed by Epoetin-alpha-induced tyrosine phosphorylation of the Janus kinase 2 (JAK2) protein kinase. Transmigration assays across Matrigel-coated filters were used to examine the effects of Epoetin-alpha on cell invasiveness. In 32 biopsies, we observed a significant association between disease progression and expression of Epo and its receptor, EpoR. Expression was highest in malignant cells, particularly within hypoxic and infiltrating tumor regions. Although both Epo and EpoR were expressed in human head and neck carcinoma cell lines, only EpoR was upregulated by hypoxia. Epoetin-alpha treatment induced prominent JAK2 phosphorylation and enhanced cell invasion. Inhibition of JAK2 phosphorylation reduced both basal and Epo-induced invasiveness. Our findings support a role for autocrine or paracrine Epo signaling in the malignant progression and local invasiveness of head and neck cancer. This mechanism may also be activated by recombinant Epo therapy and could potentially produce detrimental effects in rhEpo-treated cancer patients.

Biopsy↗
PubMed2004

Immune responses of breast cancer patients to mutated epidermal growth factor receptor (EGF-RvIII, Delta EGF-R, and de2-7 EGF-R).

Mutated epidermal growth factor receptor (EGF-RvIII, DeltaEGF-R, and de2-7 EGF-R) is the result of an 801-bp deletion within the extracellular domain of wild-type EGF-R and is expressed by breast carcinomas, but not by normal breast tissues. EGF-RvIII is expressed both on the surface and in the cytoplasm of tumor cells. Thus, EGF-RvIII is a potential tumor-specific target for both Abs and T cells. However, it is not known whether breast cancer patients can raise immune responses to EGF-RvIII expressed by their tumors. The demonstration of EGF-RvIII-specific immune responses in patients would suggest that immunization of patients with EGF-RvIII vaccines is feasible, because these vaccines may boost a pre-existing immune response. We have evaluated humoral and cellular immune responses to EGF-RvIII in 16 breast cancer patients and three healthy donors. Seven of 16 patients developed EGF-RvIII-specific Abs that bound to isolated EGF-RvIII protein or the protein expressed by EGF-RvIII-transfected mouse fibroblasts. The Abs that bound to EGF-RvIII did not bind to wild-type EGF-R, and anti-EGF-RvIII Abs were not found in the sera of healthy donors. Three patients had EGF-RvIII peptide-specific lymphoproliferative responses, and two of these patients also had humoral immune responses. Humoral and cellular immune responses correlated with EGF-RvIII expression by patients' tumors in most cases. These studies demonstrate that breast cancer patients specifically recognize EGF-RvIII with an overall immune response rate of 50%, suggesting that patients may benefit from vaccination against EGF-RvIII, boosting pre-existing immune responses.

Adult↗
PubMed2004

Autocrine erythropoietin signaling inhibits hypoxia-induced apoptosis in human breast carcinoma cells.

Disordered perfusion and the resulting hypoxia are important features conferring tumor heterogeneity, which may contribute to relapse. Hypoxic tumor cells have been associated with resistance both to radiation and to cytotoxic drugs. Hypoxia may also serve as a selection pressure in tumors by promoting apoptosis of some cells and expanding variants with decreased apoptotic potential, and thus play a role in the development of a more aggressive phenotype. Erythropoietin (Epo), induced by hypoxia, controls erythropoiesis and plays a role in protection of neurons from hypoxic damage. We have recently demonstrated hypoxia-stimulated expression of Epo and Epo receptor (EpoR) in human breast and cervix cancers, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of carcinomas. In the current study we provide evidence that increased autocrine Epo signaling induced by moderate levels of hypoxia inhibits hypoxia-induced apoptosis and promotes survival in MCF-7 human breast cancer cells. The anti-apoptotic effect of Epo correlates with upregulation of bcl-2 and bcl-XL, suggesting a mechanism similar to those described in hematopoietic cells. The resulting decreased apoptotic potential of hypoxic tumor cells may contribute to increased aggressiveness and therapy resistance of breast cancers.

Apoptosis↗