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Adrian L Harris

Publications and source records attributed to Adrian L Harris.

At least 73 records · Page 4Linked to original sources
PubMed2004

Vascularization and expression of hypoxia-related tissue factors in intracranial ependymoma and their impact on patient survival.

We investigated angiogenic patterns and expression of hypoxia-related tissue factors and their prognostic impact in 100 cases of intracranial ependymoma. Angiogenic patterns were evaluated by anti-CD34 immunolabeling. Hypoxia-related factors carbonic anhydrase 9 (CA9) and hypoxia-inducible factor 1 alpha (HIF-1alpha) were visualized by immunohistochemistry, and vascular endothelial growth factor (VEGF) mRNA by in situ hybridization. Expression patterns of VEGF and CA9 are similar with regard to distribution (perinecrotic) and extent. HIF-1alpha expression occurs in a significantly smaller fraction of cases and only in a few tumor cells without clear association with necrosis. Expression of VEGF and CA9, but not HIF-1alpha, is associated with a bizarre angiogenic subtype. Combined expression of two or three hypoxia markers (high hypoxia score) associates with presence of necrosis, high proliferation index, bizarre vascular pattern, and increased cellularity. Univariate analysis indicated that patients with high hypoxia score had significantly shorter survival. On multivariate analysis, only proliferation index and extent of resection remained independent predictive factors. We conclude that bizarre vascular pattern, necrosis and high hypoxia score are frequently detectable in intracranial ependymoma, but seem less important for patient outcome than tumor cell proliferation.

Adolescent↗
PubMed2004

Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix.

PURPOSE: Hypoxia-inducible factor (HIF)-1alpha expression was studied retrospectively in locally advanced carcinoma of the cervix in relation to other methods for measuring/assessing tumor hypoxia and outcome after radiotherapy. EXPERIMENTAL DESIGN: HIF-1alpha expression was examined in formalin-fixed tumor biopsies using a semiquantitative scoring system and correlated with measurements of hypoxia obtained using oxygen electrodes, pimonidazole staining, and carbonic anhydrase 9. RESULTS: High HIF-1alpha expression showed a weak correlation with low pO2 (r = -0.26; P = 0.030; n = 72). Weak significant correlations were found between HIF-1alpha and pimonidazole staining (r = 0.34; P = 0.040; n = 36) and carbonic anhydrase IX (r = 0.27; P = 0.001; n = 160). There was no relationship with surviving fraction at 2 Gy. The relationship between HIF-1alpha expression and radiotherapy outcome was examined in 99 patients. HIF-1alpha expression did not correlate with disease stage, grade, tumor size, and patient age. HIF-1alpha alone was not a significant prognostic factor for disease-free survival, metastasis-free survival, or local recurrence-free survival. High HIF-1alpha expression tended to be associated with poor outcome in small tumors but good outcome in large tumors, with statistically significant interactions between HIF-1alpha and tumor size for survival (P = 0.046) and local control (P = 0.009). CONCLUSIONS: In this study, HIF-1alpha had no prognostic significance in locally advanced carcinoma of the cervix. The possible switch in large tumors for an association between high HIF-1alpha expression and good outcome might relate to tumor size-related changes in the balance of genes up-regulated by HIF-1alpha. Whereas angiogenesis-promoting genes might be preferentially up-regulated in small tumors, proapoptotic genes might be induced in large tumors. This hypothesis needs testing in future work.

Antigens, Neoplasm↗
PubMed2004

Increased angiogenesis and lymphangiogenesis in inflammatory versus noninflammatory breast cancer by real-time reverse transcriptase-PCR gene expression quantification.

PURPOSE: Inflammatory breast cancer is a distinct and aggressive form of locally advanced breast cancer with unique clinical and pathological features. Recently, histologic evidence of intense angiogenesis was found in inflammatory breast cancer specimens. The aim of this study was to confirm the angiogenic phenotype of inflammatory breast cancer and to investigate its potential to induce lymphangiogenesis. EXPERIMENTAL DESIGN: Real-time quantitative reverse transcriptase-PCR was used to measure levels of mRNA of tumor angiogenesis and lymphangiogenesis-related factors [vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D, Flt-1, KDR, Flt-4, Ang-1, Ang-2, Tie-1, Tie-2, cyclooxygenase-2, fibroblast growth factor-2 (FGF-2), Egr-1, Prox-1, and LYVE-1] in tumor specimens of 16 inflammatory breast cancer and 20 noninflammatory breast cancer patients. Tissue microarray technology and immunohistochemistry were used to study differential protein expression of some of the angiogenic factors in inflammatory breast cancer and noninflammatory breast cancer. Active lymphangiogenesis was further assessed by measuring lymphatic endothelial cell proliferation. RESULTS: Inflammatory breast cancer specimens had significantly higher mRNA expression levels than noninflammatory breast cancer specimens of the following genes: KDR (P = 0.033), Ang-1, (P = 0.0001), Tie-1 (P = 0.001), Tie-2 (P = 0.001), FGF-2 (P = 0.002), VEGF-C (P = 0.001), VEGF-D (P = 0.012), Flt-4 (P = 0.001), Prox-1 (P = 0.005), and LYVE-1 (P = 0.013). High mRNA levels of FGF-2 and cyclooxygenase-2 corresponded to increased protein expression by immunohistochemistry. Inflammatory breast cancer specimens contained significantly higher fractions of proliferating lymphatic endothelial cells than noninflammatory breast cancer specimens (P = 0.033). CONCLUSIONS: Using real-time quantitative reverse transcriptase-PCR and immunohistochemistry, we confirmed the intense angiogenic activity in inflammatory breast cancer and demonstrated the presence of active lymphangiogenesis in inflammatory breast cancer. This may help explain the high metastatic potential of inflammatory breast cancer by lymphatic and hematogenous route. Both pathways are potential targets for the treatment of inflammatory breast cancer.

Adult↗
PubMed2004

c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent.

c-erbB-2-positive breast carcinomas are highly aggressive tumors. In vitro data on breast cell lines showed that c-erbB-2 enhanced translational efficiency of hypoxia inducible factor-1alpha (HIF1alpha) production (Laughner et al., Mol Cell Biol 2001;21:3995-4005). We investigated the clinical correlate of this observation to assess whether c-erbB-2 expression was related to HIF1alpha expression, angiogenesis, and prognosis. A series of 180 breast carcinomas of known c-erbB-2 status (90 c-erbB-2-positive and 90 c-erbB-2-negative carcinomas) were stained immunohistochemically for HIF1alpha and CD31 endothelial cell antigen. c-erbB-2 positivity was clearly related to HIF1alpha protein expression and high angiogenesis. However, prognosis was decreased only in cases with simultaneous c-erbB-2 and HIF1alpha expression. If activation of c-erbB-2 in humans results in overexpression of HIF1alpha independently of conditions of hypoxia, as occur in experimental studies, this interaction may represent a main pathway conferring clinical aggressiveness to c-erbB-2-positive breast tumors.

Biomarkers, Tumor↗
PubMed2004

Expression of hypoxia-related tissue factors correlates with diminished survival of adjuvantly treated patients with chromosome 1p aberrant oligodendroglial neoplasms and therapeutic implications.

PURPOSE: Oligodendroglial neoplasms with chromosome 1p deletion are chemosensitive, and stratified adjuvant therapies have been proposed on the basis of 1p status. In this study, we evaluated expression of hypoxia-related factors and its influence on survival in oligodendroglial brain tumors with chromosome 1p aberrations. EXPERIMENTAL DESIGN: Forty-four primary and 16 recurrent oligodendroglial neoplasms with 1p aberrations (deletion or imbalance) were investigated immunohistochemically for expression of hypoxia-inducible factor 1alpha and carbonic anhydrase-9. We used in situ hybridization to investigate expression of vascular endothelial growth factor-mRNA. We defined as "low hypoxia score" expression of no or only one marker and as "high hypoxia score" expression of two or three markers. The predominant vascular patterns of tumors were defined as classic or bizarre vascular formations, based on anti-CD34-immunostaining. RESULTS: High hypoxia score was evident in 16 of 44 (36.4%) primary tumor specimens and in 14 of 16 (87.5%) recurrent tumors (P = 0.001). High hypoxia score was associated with the presence of bizarre vascular proliferations and WHO grade III. In the subgroup of patients who received adjuvant therapy, univariate analysis showed significantly shorter survival of patients with high hypoxia score (n = 27; P = 0.0145). For all of the primary tumors, hypoxia score was an independent prognostic factor (P = 0.045). CONCLUSIONS: A fraction of oligodendroglial neoplasms with 1p aberrations shows evidence of tissue hypoxia, which significantly influences survival of patients receiving adjuvant therapy. Evaluation of tissue hypoxia could become useful for recruitment of patients for individualized therapy strategies, e.g., selection of patients with hypoxic tumors for hyperbaric oxygenation preceding radiotherapy.

Adult↗
PubMed2004

A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer.

PURPOSE: Tumor necrosis factor (TNF) alpha is a key player in the tumor microenvironment and is involved in the pathogenesis of breast cancer. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-alpha and renders it biologically unavailable. In the current study, we sought to determine the toxicity, biological activity, and therapeutic efficacy of Etanercept in metastatic breast cancer. EXPERIMENTAL DESIGN: We initiated a Phase II, nonrandomized, open-labeled study in patients with progressive metastatic breast cancer refractory to conventional therapy (Phase I toxicity data were available in patients with rheumatoid arthritis). Etanercept was administered subcutaneously at a dose of 25 mg twice weekly until disease progression. RESULTS: Sixteen patients were recruited [median age 53 years (range, 34 to 74)]. A total of 141.6 weeks of therapy was administered (median of 8.1 weeks). Seven patients received > or =12 weeks of therapy. The most common side effects were injection site reactions (6), fatigue (5), loss of appetite (2), nausea (1), headache (1), and dizziness (1). Brief period of disease stabilization was seen in 1 patient lasting for 16.4 weeks. Immunoreactive TNF-alpha was elevated within 24 hours of therapy and persisted until the end of treatment (days 7, 28, 56, and 84). Phytohemagglutinin stimulates the production of interleukin-6 and CCL2 in peripheral blood cells, and the ability of Etanercept to modulate this response was assessed in a cytokine release assay. A consistent decrease in interleukin-6 and CCL2 level was seen compared with pretreatment values in serial blood samples (days 1, 7, 28, 56, and 84). CONCLUSIONS: Our study shows the safety and biological activity of Etanercept in breast cancer and provides data to assess pharmacodynamic endpoints of different schedules of Etanercept and combinations with chemotherapy or other biological therapies.

Adult↗
PubMed2004

c-Myc interacts with hypoxia to induce angiogenesis in vivo by a vascular endothelial growth factor-dependent mechanism.

The proto-oncogene c-myc is involved in the regulation of cell proliferation, differentiation, and apoptosis. In this study, we used an inducible transgenic mouse model in which c-Myc was targeted to the epidermis and, after activation, gave rise to hyperplastic and dysplastic skin lesions and to dermal angiogenesis, involving both vascular endothelial growth factor (VEGF) receptor-1 and VEGF receptor-2. After c-Myc activation, VEGF mRNA was expressed in postmitotic keratinocytes where it colocalized with transgene expression and areas of tissue hypoxia, suggesting a role of hypoxia in VEGF induction. In vitro, c-Myc activation alone was able to induce VEGF protein release and in conjunction with hypoxia, c-Myc activation further increased VEGF protein. Blocking VEGF signaling in vivo significantly reduced dermal angiogenesis, demonstrating the importance of VEGF as a mediating factor for the c-Myc-induced angiogenic phenotype.

Animals↗
PubMed2004

Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion.

Carbonic anhydrase IX (CAIX) is a membrane-associated carbonic anhydrase (CA), strongly induced by hypoxia. CAIX is overexpressed in a variety of tumor types and associated with increased metastasis and poor prognosis. An inhibitor of CAs, acetazolamide has been reported to inhibit invasion. We used RNA interference (RNAi) to examine the function of CAIX in MDA468 and MDA231 breast carcinoma cells, which express high levels of CAIX under hypoxia. Hypoxia-induced CA activity was completely blocked by specific RNAi (P < 0.01). RNAi-treated cells showed growth delay in dense monolayer culture and a 50% reduction in clonogenic survival under hypoxia. In the MDA468 cells, there was no effect of RNAi treatment on invasion. In a cell line that did not induce CAIX under hypoxia, RT112, we found no effect on the ability of cells transfected with CAIX to invade or migrate. Thus, CAIX plays an important role in the growth and survival of tumor cells under normoxia and hypoxia, making it a potential target for cancer therapy, but is not involved in invasion.

Acetazolamide↗
PubMed2004

CITED4 inhibits hypoxia-activated transcription in cancer cells, and its cytoplasmic location in breast cancer is associated with elevated expression of tumor cell hypoxia-inducible factor 1alpha.

The interaction of hypoxia-inducible factor 1alpha and the CH1 domain of the transcriptional coactivator p300/CBP is necessary for the expression of hypoxia responsive genes and tumor angiogenesis. The transcription factor CITED2 binds p300/CBP at the CH1 domain and functions as a negative regulator of hypoxia signaling by competing with hypoxia-inducible factor 1alpha. CITED4, a recently identified member of the CITED family, binds p300/CBP via the CH1 domain and functions as a coactivator for transcription factor AP-2. Here, we show that CITED4 blocks the binding of hypoxia-inducible factor 1alpha to p300 in vitro and inhibits hypoxia-inducible factor-1alpha transactivation and hypoxia-mediated reporter gene activation. These studies suggest that CITED4 might function as an inhibitor of hypoxia-inducible factor 1alpha. To explore the function of CITED4 in breast cancer, we determined its expression in normal, in situ and invasive breast cancers. We also correlated its expression in 286 invasive breast tumors with clinicopathological, hypoxia markers and survival. In contrast to the nuclear localization of CITED4 in normal breast tissue, breast tumors were characterized by cytoplasmic and nuclear localization. Nuclear CITED4 expression was significantly inversely associated with tumor hypoxia-inducible factor 1alpha (P < 0.05), tumor size (P = 0.03), tumor grade (P = 0.0001), and Chalkley vessel count (P = 0.04). CITED4 showed no significant correlation with patient age (P = 0.45), estrogen receptor (P = 0.11), or epidermal growth factor receptor (P = 0.48). These results show that breast cancer development is characterized by either nuclear loss or cytoplasmic translocation of CITED4, with consequent loss of hypoxia-inducible factor-1alpha transcriptional antagonist activity. This may be an important mechanism by which tumors enhance hypoxia-inducible factor expression and result in an aggressive phenotype.

Amino Acid Sequence↗
PubMed2004

BNIP3 expression is linked with hypoxia-regulated protein expression and with poor prognosis in non-small cell lung cancer.

BNIP3 is a proapoptotic protein regulated by hypoxia-inducible factor 1. We analyzed BNIP3 expression in 105 tumor samples from early operable, non-small lung cancer and the relationship of expression to hypoxia-inducible factor 1alpha, other hypoxia-regulated pathways, and prognosis. There was strong cytoplasmic expression in >10% of cells in 40 of 105 cases. BNIP3 expression was associated significantly with high hypoxia-inducible factor 1alpha (P = 0.003), carbonic anhydrase 9 (P = 0.04), and was inversely associated with bcl-2 expression (P = 0.009). High BNIP3 expression was a major independent factor for overall survival. Thus, high expression of a hypoxia regulated proapoptotic pathway was associated with a selection of an aggressive phenotype in vivo.

Adenocarcinoma↗
PubMed2004

Hypoxia-inducible factor-1 alpha in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways.

Hypoxia-inducible factor (HIF)-1 alpha is the regulatory subunit of HIF-1 that is stabilized under hypoxic conditions. Under different circumstances, HIF-1 alpha may promote both tumorigenesis and apoptosis. There is conflicting data on the importance of HIF-1 alpha as a prognostic factor. This study evaluated HIF-1 alpha expression in 172 consecutive patients with stage I-IIIA non small cell lung cancer (NSCLC) using standard immunohistochemical techniques. The extent of HIF-1 alpha nuclear immunostaining was determined using light microscopy and the results were analyzed using the median (5%) as a low cut-point and 60% as a high positive cut-point. Using the low cut-point, positive associations were found with epidermal growth factor receptor (EGFR; p = 0.01), matrix metalloproteinase (MMP)-9 (p = 0.003), membranous (p < 0.001) and perinuclear (p = 0.004) carbonic anhydrase (CA) IX, p53 (p = 0.008), T-stage (p = 0.042), tumor necrosis (TN; p < 0.001) and squamous histology (p < 0.001). No significant association was found with Bcl-2 or either N- or overall TMN stage or prognosis. When the high positive cut-point was used, HIF-1 alpha was associated with a poor prognosis (p = 0.034). In conclusion, the associations with EGFR, MMP-9, p53 and CA IX suggest that these factors may either regulate or be regulated by HIF-1 alpha. The association with TN and squamous-type histology, which is relatively more necrotic than other NSCLC types, reflects the role of hypoxia in the regulation of HIF-1 alpha. The prognostic data may reflect a change in the behavior of HIF-1 alpha in increasingly hypoxic environments.

Adult↗
PubMed2004

Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor.

Hypoxia-inducible factor (HIF) is a transcriptional regulator that plays a key role in many aspects of oxygen homeostasis. The heterodimeric HIF complex is regulated by proteolysis of its alpha-subunits, following oxygen-dependent hydroxylation of specific prolyl residues. Although three HIF prolyl hydroxylases, PHD1, PHD2, and PHD3, have been identified that have the potential to catalyze this reaction, the contribution of each isoform to the physiological regulation of HIF remains uncertain. Here we show using suppression by small interference RNA that each of the three PHD isoforms contributes in a non-redundant manner to the regulation of both HIF-1alpha and HIF-2alpha subunits and that the contribution of each PHD under particular culture conditions is strongly dependent on the abundance of the enzyme. Thus in different cell types, isoform-specific patterns of PHD induction by hypoxia and estrogen alter both the relative abundance of the PHDs and their relative contribution to the regulation of HIF. In addition, the PHDs manifest specificity for different prolyl hydroxylation sites within each HIF-alpha subunit, and a degree of selectively between HIF-1alpha and HIF-2alpha isoforms, indicating that differential PHD inhibition has the potential to selectively alter the characteristics of HIF activation.

Animals↗
PubMed2004

Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases.

The vasodilator hydralazine, used clinically in cardiovascular therapy, relaxes arterial smooth muscle by inhibiting accumulation of intracellular free Ca2+ via an unidentified primary target. Collagen prolyl hydroxylase is a known target of hydralazine. We therefore investigated whether inhibition of other members of this enzyme family, namely the hypoxia-inducible factor (HIF)-regulating O2-dependent prolyl hydroxylase domain (PHD) enzymes, could represent a novel mechanism of action. Hydralazine induced rapid and transient expression of HIF-1alpha and downstream targets of HIF (endothelin-1, adrenomedullin, haem oxygenase 1, and vascular endothelial growth factor [VEGF]) in endothelial and smooth muscle cells and induced endothelial cell-specific proliferation. Hydralazine dose-dependently inhibited PHD activity and induced nonhydroxylated HIF-1alpha, evidence for HIF stabilization specifically by inhibition of PHD enzyme activity. In vivo, hydralazine induced HIF-1alpha and VEGF protein in tissue extracts and elevated plasma VEGF levels. In sponge angiogenesis assays, hydralazine increased stromal cell infiltration and blood vessel density versus control animals. Thus, hydralazine activates the HIF pathway through inhibition of PHD activity and initiates a pro-angiogenic phenotype. This represents a novel mechanism of action for hydralazine and presents HIF as a potential target for treatment of ischemic disease.

Adrenomedullin↗
PubMed2004

Noninvasive measurements of capecitabine metabolism in bladder tumors overexpressing thymidine phosphorylase by fluorine-19 magnetic resonance spectroscopy.

PURPOSE: Previous studies have shown that tumor response to capecitabine strongly correlates with tumor thymidine phosphorylase (TP). The aims of our study were to (a). investigate the pharmacological role of TP by measuring the pharmacokinetics (PK) of capecitabine in a human bladder tumor model that was characterized by the overexpression of TP and (b). develop the use of PK measurements for capecitabine by fluorine-19 magnetic resonance spectroscopy as a noninvasive surrogate marker for determining TP levels in tumors and for predicting tumor response to capecitabine in patients. EXPERIMENTAL DESIGN: TP overexpressing (2T10) and control tumors were grown s.c. in nude mice. Mice were given a dose of capecitabine or 5'-deoxy-5-fluorouridine (5'DFUR). (19)F tumor spectra were acquired for determination of rate constants of capecitabine breakdown and buildup and subsequent breakdown of intermediates, 5'-deoxy-5-fluorocytidine (5'DFCR) and 5'DFUR. The rate constant of 5'DFUR breakdown was also evaluated. RESULTS: The rate constant of breakdown of intermediates was significantly faster in 2T10 tumors than controls (P < 0.003). No significant differences in the rate of capecitabine breakdown or intermediate buildup were observed. The rate constant of 5'DFUR breakdown in the 2T10 tumors was doubled compared with controls (P < 0.001). CONCLUSIONS: This study confirmed the expected pathway of capecitabine metabolism and showed that the level of TP was related to the rate of 5'DFUR conversion. Using in vivo fluorine-19 magnetic resonance spectroscopy to mea-sure the PK of capecitabine and its intermediate metabolites in tumors may provide a noninvasive surrogate method for determining TP levels in tumors and for predicting tumor response to capecitabine in patients.

Animals↗
PubMed2004

Expression of the forkhead transcription factor FOXP1 is associated with estrogen receptor alpha and improved survival in primary human breast carcinomas.

PURPOSE: The FOXP1 protein belongs to a functionally diverse family of winged-helix or forkhead transcription factors that have diverse roles in cellular proliferation, differentiation, and neoplastic transformation. The FOXP1 gene, which maps to 3p14, shows common loss of heterozygosity in breast tumors and is a candidate tumor suppressor gene. However, its role in breast cancer is unknown. EXPERIMENTAL DESIGN: We have therefore investigated the pattern of FOXP1 expression in whole sections from normal (n = 16) and neoplastic (n = 90) breast tissues and correlated the level of expression in 283 invasive breast carcinomas on tissue microarrays with clinicopathological factors and survival. Because a relationship with estrogen receptor (ER) was identified, estrogen (17beta-estradiol) regulation and ER/FOXP1 colocalization was also investigated. RESULTS: Expression of FOXP1 was significantly positively associated with ER (P = 0.03) and negatively with epidermal growth factor receptor (P = 0.01) but no association with age (P = 0.91), lymph node status (P = 0.94), size (P = 0.76), or grade (P = 0.22). In a multivariate analysis of survival, FOXP1 expression was associated with a significantly improved relapse-free (P = 0.03) and borderline overall (P = 0.09) survival. Unlike normal breast, there was common coexpression of FOXP1 and ER in cell lines and tumors, but no 17beta-estradiol (10(-9) m) regulation of FOXP1 in MCF-7 cells was demonstrated. CONCLUSIONS: Our findings support a role for FOXP1 as a potential ER coregulator in human breast carcinoma and suggest that it may also independently regulate additional important pathways that control the progression of breast cancer.

Adult↗
PubMed2004

Hypoxia-activated tumor pathways of angiogenesis and pH regulation independent of anemia in head-and-neck cancer.

PURPOSE: Anemia is considered a major factor that counteracts the efficacy of radiotherapy, presumably because of reduced oxygen availability that leads to tumor hypoxia. Nevertheless, anemia is not the only factor defining oxygen availability, because a poor and/or immature vascular network may prevent blood flow and tumor oxygenation. Furthermore, the ability of tumors to upregulate hypoxia-regulated molecular pathways may affect radiosensitivity by mechanisms independent of the traditional concept of "oxygen effect." METHODS AND MATERIALS: In this study, we investigated whether the preoperative blood hemoglobin levels affect the activation status of hypoxia/angiogenic pathways (hypoxia inducible factors [HIF1 alpha and HIF2 alpha], carbonic anhydrase 9, differentiated embryo-chondrocyte protein, vascular endothelial growth factor, and microvessel density), in squamous cell head-and-neck cancer. RESULTS: Hypoxia/angiogenesis pathways were equally activated in tumors, independent of the patient's hemoglobin levels. The expression of HIF alphas was associated with microvessel density (p = 0.01). CONCLUSION: In the present study, we failed to show that a patient's anemia is a main contributor to the activation of hypoxia-regulated molecular pathways in squamous cell head-and-neck cancer. Impaired intratumoral blood flow or tumor-related gene/protein pathologic features may account for this finding. Targeting the hypoxia-regulated molecular cascade emerged as a complementary radiosensitization strategy for a large group of patients with hypoxic tumors, who are unlikely to benefit from conventional approaches aiming to improve intratumoral oxygen delivery through anemia correction.

Anemia↗
PubMed2004

Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines.

The nuclear receptor peroxisome proliferator-activated receptor delta [PPARdelta/beta (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARdelta by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARdelta selective agonists. Activation of PPARdelta with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPARdelta agonist, GW501516. Conditional expression of PPARdelta in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPARdelta in the proliferative response to this drug. Activation of PPARdelta in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor alpha (VEGFalpha) and its receptor, FLT-1, thus, suggesting that PPARdelta may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGFalpha and FLT-1 in these cells. Our observations provide the first evidence that activation of PPARdelta can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPARdelta antagonists may be of therapeutic value in the treatment of breast and prostate cancer.

Breast Neoplasms↗