Biomedical subjects

Cornelia Leo

Publications and source records attributed to Cornelia Leo.

10 recordsLinked to original sources

PubMed2006

Expression of erythropoietin and erythropoietin receptor in cervical cancer and relationship to survival, hypoxia, and apoptosis.

PURPOSE: Physiologically, hypoxia induces the expression of erythropoietin (Epo) in adult kidney cells. Epo, in turn, acts on the Epo receptor (EpoR) in RBC precursors to stimulate growth and prevent apoptosis. Because hypoxia plays a major role in the malignant progression of tumors and Epo and its receptors have also been detected in malignant tumors, we investigated the expression of Epo and EpoR and their relationship with hypoxia, proliferation, apoptosis, and clinicopathologic variables in cervical cancer. EXPERIMENTAL DESIGN: Intratumoral oxygen measurement and needle biopsies of the tumors were done in 48 patients with cervical cancer. The obtained tissue was analyzed by immunohistochemistry with antibodies against Epo, EpoR, and Ki-67 as well as by terminal deoxynucleotidyl transferase-mediated deoxyuracil triphosphate nick-end labeling assays. RESULTS: Epo and EpoR were expressed in 88% and 92% of samples, respectively. Cervical cancers with higher Epo expression showed a significantly reduced overall survival (3 years, 50.0% versus 80.6%; P = 0.0084). Epo and EpoR expression correlated significantly with apoptosis (r = 0.49, P = 0.001 and r = 0.36, P = 0.021). Furthermore, EpoR expression correlated significantly with tumor size (r = 0.32, P = 0.032) and was significantly associated with the presence of lymphovascular space involvement (P = 0.037). However, we observed no correlation between Epo or EpoR expression and intratumoral hypoxia, although in well-oxygenated tumors, EpoR localized significantly more often to the invasion front (P = 0.047). CONCLUSIONS: This study analyzes Epo/EpoR expression and their relationship with intratumoral pO(2) levels as well as with survival in patients with cervical cancer. The data suggest a critical role of the endogenous Epo/EpoR system in cervical cancer.

Adult↗

PubMed2006

Tumor hypoxia and expression of c-met in cervical cancer.

OBJECTIVES: Hypoxia enhances malignant progression by promoting the development of metastases and increasing invasiveness. One key regulator that controls growth, invasion and metastasis in cancer cells is the growth factor receptor c-met. The aim of this study, therefore, was to investigate the expression of the c-met protooncogene in cervical cancers in relation to intratumoral hypoxia levels and to clinico-pathological parameters. METHODS: 43 Patients with cervical cancer were subjected to intratumoral pO(2) measurement with the Eppendorf electrode and biopsies were taken. The tissue was subsequently analyzed by immunohistochemistry with an anti-c-met antibody. RESULTS: c-met was expressed in 72% of cervical cancers. There was a significantly stronger expression in poorly differentiated tumors (r=0.4, p=0.008). Furthermore, c-met expression was significantly associated with a spray-like pattern of invasion (p=0.008). However, there was no significant relationship between c-met expression and intratumoral hypoxia, pT stage, FIGO stage, lymphovascular space involvement, tumor size or overall survival. CONCLUSIONS: Although c-met has been shown to be hypoxia-induced in vitro, our results suggest that it is not the mediator of deleterious effects of hypoxia on clinical outcome in cervical cancer.

Adult↗

PubMed2006

Mixed small cell carcinomas of the uterine cervix: prognostic impact of focal neuroendocrine differentiation but not of Ki-67 labeling index.

Small cell neuroendocrine carcinomas sometimes represent a non-small cell component. Because of infection with the high-risk human papillomavirus of small cell carcinomas (SmCCs), several host cell regulatory proteins are altered, thus causing altered proliferative activity. Knowledge regarding the prognostic impact of focal neuroendocrine differentiation in mixed SmCCs and the value of proliferative activity in these tumors is very limited. Small cell carcinomas were selected for immunohistochemical staining with neuroendocrine markers and Ki-67. In cases with mixed tumors, the percentage of the SmCC component was calculated and correlated with survival. Of 677 tumors, 9 (1.3%) were classified as SmCCs after Grimelius staining (8/9 positive tumors) and immunohistochemical reaction against neuron-specific enolase, chromogranin A, synaptophysin (7/9 positive tumors), and CD56 (8/9 positive tumors); all specimens were positive for at least 2 of these. CD99 staining was completely negative. Two thirds of the SmCCs showed non-small cell differentiation. Four patients died of the tumor after a median time of 36.7 months (range, 15-56 months). Even an SmCC component of 17% was associated with a fatal course. Small cell carcinoma represented a significantly lower proliferation (Ki-67 labeling index) than did the non-small cell component in the same tumor (12.8% vs 70.8%; P < .001). Even a small SmCC component in mixed carcinomas of the uterine cervix was associated with adverse outcome. Proliferative activity, determined by Ki-67 labeling index, is of no prognostic value.

Adult↗

PubMed2006

p16, p14, p53, cyclin D1, and steroid hormone receptor expression and human papillomaviruses analysis in primary squamous cell carcinoma of the endometrium.

Pathogenetically, endometrioid adenocarcinomas of the endometrium are associated with hyperestrogenism and serous papillary carcinomas with alterations of p53. The etiology of primary endometrial squamous cell carcinoma (ESCC), however, is speculative. The purpose of this study was to evaluate the role of p14, p16, p53, cyclin D1, steroid hormone receptors, and human papillomaviruses (HPV) infection in the pathogenesis of primary endometrial squamous cell carcinoma. The expression of p16, p14, p53, cyclin D1, and steroid hormone receptors (estrogen, progesterone, and androgen) was examined immunohistochemically in 8 primary ESCCs. HPV analysis was performed using general primers and HPV typing. The median age of the patients was 62.1 years. Four cases showed positive nuclear and cytoplasmic p16 staining in an insular pattern, and 1 case nuclear positivity for p53 and estrogen receptors, respectively. Four of 8 cases were positive for progesterone receptor analysis and cyclin D1. All cases were negative for p14 and androgen receptor staining. All but one case were negative for HPV analysis. Five patients were alive with and without evidence of disease after a mean follow-up of 6.1 years. The results of this study suggest that alterations of the p16 pathway may play an etiologic role in at least a proportion of the ESCC, but without any association to HPV infection. Factors known to play a pathogenetic role in types 1 and 2 of endometrial carcinomas are not associated with primary ESCC. However, prognostically, ESCCs are more related to type 1 cancers.

Adult↗

PubMed2006

Juxtatumoral desmoplastic stromal reaction is associated with high tumor cell dissociation in squamous cell carcinomas of the uterine cervix.

There are different types of tumoral growth patterns invading host tissue. During tumor infiltration, cancer cells not only destroy the pre-existing extracellular matrix, but usually induce new matrix formation by activating the peritumoral stromal cells; that is, desmoplastic stromal reaction (DSR) at the front of invasion (juxtatumoral stroma). This study evaluates the association between different types of invasion and DSR. Eighty-eight squamous cell carcinomas (Fédération Internationale de Gynécologie et d'Obstétrique [FIGO] stage IB to IV) were evaluated histologically for different patterns of invasion (PI) using a 3-level scoring system (pushing, finger-like, and spray-like). Desmoplastic stromal reaction was scored from none to weak, moderate, or strong. The pattern of invasion and DSR were compared with patients' age, FIGO stage, clinical tumor size, tumor grade, and the presence of lymphovascular space involvement. Finger-like PI was the most common (72.7%), followed by the spray-like PI (27.3%), whereas pushing PI was not seen. Of the tumors, 23.9% showed no DSR; 51.1%, weak; 14.8%, moderate; and 10.2%, strong DSR. Tumors with spray-like PI showed a significantly stronger desmoplastic reaction compared with the finger-like PI (P < .0001) and were significantly associated with poor tumor cell differentiation (P = .018). Moderate or strong DSR was associated with G2 and G3 carcinomas (P = .027). No correlation was seen neither for PI and DSR to lymphovascular space involvement, FIGO stage, and tumor size. The intensity of DSR, as understood in the context of a remodeling of the juxtatumoral stroma to the infiltrative tumor growth, might be indicative of a highly dissociative tumor growth and is correlated to poorly differentiated tumors.

Adult↗

PubMed2006

The status of cyclooxygenase-2 expression in ductal carcinoma in situ lesions and invasive breast cancer correlates to cyclooxygenase-2 expression in normal breast tissue.

OBJECTIVES: There is a paucity of data on cyclooxygenase (COX)-2 expression in normal breast tissue and on the changes in COX-2 expression from normal tissue via ductal carcinoma in situ (DCIS) lesions to invasive cancer. The aim of this study, therefore, was to investigate COX-2 protein expression in normal breast tissue, DCIS, and invasive breast cancer in samples from the same patients. METHODS: In 39 patients, we investigated and compared COX-2 expression in paired samples of invasive cancer and normal adjacent breast epithelium by immunohistochemistry with a monoclonal COX-2 antibody. Furthermore, in 29 of these cases, we also analyzed a concomitant DCIS lesion. RESULTS: Patients without COX-2 expression in normal breast tissue also do not express COX-2 in invasive breast cancer and in DCIS lesions, respectively. Conversely, COX-2 expression in normal breast tissue was an indicator for COX-2 expression in the paired breast tumors. There was no significant correlation between COX-2 expression and pathologic tumor stage, nodal status, hormone receptor status, tumor size, grading, and lymphovascular space involvement. CONCLUSIONS: This is the largest study to date investigating COX-2 in paired samples of breast tumors and normal adjacent breast tissue. Our data are consistent with the hypothesis that COX-2 overexpression is an early event in breast carcinogenesis.

Adult↗

PubMed2006

p16, p14, p53, and cyclin D1 expression and HPV analysis in small cell carcinomas of the uterine cervix.

Small cell carcinomas (SmCCs) of the uterine cervix are rare tumors. The knowledge regarding protein expression of several checkpoint candidates of cell cycle regulation is limited. Surgically treated SmCCs were selected from our files for immunohistochemical staining (neuroendocrine markers, p53, p16, p14, and cyclin D1). Polymerase chain reaction analysis, using general primers, was performed for human papillomavirus analysis. Nine of 677 tumors (1.3%) were classified as SmCCs after Grimelius staining (8/9 tumors positive) and immunohistochemical reaction against neurone-specific enolase, chromogranin A, synaptophysin (7/9 positive tumors), and CD 56 (8/9 positive tumors). All specimens were positive for at least two of the above. Two SmCCs were p53 positive and one case was p14 positive. Cyclin D1 staining was completely negative. All cases showed strong nuclear and/or cytoplasmic p16-immunostaining. Seven tumors represented human papillomavirus positivity for high-risk types. Four patients died of the tumor after a median time of 36.7 months (range, 15-56 months), representing a 5-year survival rate of 56%. The results suggest that p16 is up-regulated or accumulated in the SmCCs of the uterine cervix, probably caused by infection with human papillomavirus. p14 inactivation is of high prevalence in SmCCs and detection rate of p53 is similar to other histologic types of cervical carcinomas.

Adult↗

PubMed2005

Expression of Apaf-1 in cervical cancer correlates with lymph node metastasis but not with intratumoral hypoxia.

OBJECTIVES: The aim of this study was to investigate the expression of the proapoptotic protein Apaf-1 in cervical cancers. Moreover, we studied its correlation to intratumoral pO(2) and to clinico-pathological parameters. METHODS: 86 patients with cervical cancer were subjected to intratumoral pO(2) measurement with the Eppendorf electrode. From these patients, cervical cancer tissue was used for immunohistochemistry with an anti-Apaf-1 antibody. RESULTS: Apaf-1 is expressed in cervical cancer. Cervical cancers with strong or moderate Apaf-1 expression had significantly less lymph node metastases at time of surgery than tumors with weak or negative Apaf-1 expression (P = 0.022). There was no significant correlation between Apaf-1 expression and intratumoral pO(2), pT stage, FIGO stage, lymphovascular space involvement, and grade. CONCLUSIONS: Loss of Apaf-1 expression may represent a marker of aggressive tumor behavior since it correlates significantly with the occurrence of lymph node metastasis in cervical cancer.

Adult↗

PubMed2004

Lack of correlation between expression of HIF-1alpha protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix.

Hypoxia inducible factor-1alpha (HIF-1alpha) has been proposed as a candidate endogenous marker of tumor hypoxia and as a molecular mediator of hypoxia-driven malignant progression and acquired treatment resistance. In this study, HIF-1alpha expression in 68 biopsies of oxygenation measurement tracks from squamous cell carcinomas of the uterine cervix of 38 patients was assessed. Expression of HIF-1alpha was commonly found to increase as a function of distance from microvessels, at the center of tumor cell aggregations, and in the vicinity of necrotic areas. However, there was no correlation of HIF-1alpha expression with median oxygen tension (oxygen partial pressure; pO2) and hypoxic fractions (hypoxic fraction < 2.5 mm Hg, hypoxic fraction < 5 mm Hg). The results indicate that HIF-1alpha should not be used as an endogenous marker of tumor hypoxia in locally advanced squamous cell carcinomas of the uterine cervix. Additionally, no significant prognostic impact of HIF-1alpha expression was found in this group of patients.

Adult↗

PubMed2004

The hypoxic tumor microenvironment and gene expression.

Solid tumors are not static entities but are constantly responding to environmental signals as they grow and develop. One mechanism by which they respond to the adverse conditions of the tumor microenvironment is through coordinated changes in gene expression. The synchronized turning of genes on and off leads to biologic adaption to the adverse oxygen-poor environment. Because tumor hypoxia can be found in almost every solid tumor, it represents one of the most pervasive microenvironmental stresses that can impact malignant progression and therapeutic response. Interestingly, tumors that exhibit robust induction of hypoxia-responsive gene expression networks show a clinically more aggressive natural history. The contribution of hypoxia-responsive gene networks to malignant response is currently under investigation. An understanding of the coordinated functions of hypoxia induced and repressed genes can lead to a better understanding of the clinical significance of the hypoxic tumor phenotype.

Apoptosis↗