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Mammary Carcinoma (mammary + carcinoma)
Selected AbstractsMetastatic mammary carcinomas with endocrine features: Potential diagnostic pitfallsDIAGNOSTIC CYTOPATHOLOGY, Issue 1 2005Anjali Saqi M.D. Abstract Mammary carcinomas with endocrine differentiation (MCED) are an uncommon subtype of breast carcinomas that are morphologically indistinguishable from low-grade endocrine neoplasms arising in other organs. Aspirates of MCED yield relatively monotonous cells with eccentrically placed nuclei containing characteristic "salt and pepper" chromatin. In the breast, these features represent MCED. In extramammary sites, the differential is more extensive, and diagnosing MCED metastates to the lung, a common location for primary and metastatic endocrine tumors, can be a challenging task, with significant clinical implications. Although primary MCED have been described extensively in the cytology literature, secondary pulmonary MCED have not been reported to the best of our knowledge. We report three cases of MCED metastatic to the lung and present the cytological and immunohistochemical features. Diagn. Cytopathol. 2005;33:49,53. © 2005 Wiley-Liss, Inc. [source] Metaplastic mammary carcinoma with osteoclastic giant cells: a cytological mimicker of fibroadenomaCYTOPATHOLOGY, Issue 6 2004S. Jogai No abstract is available for this article. [source] The expression of Wilms' tumour-1 and Ca125 in invasive micropapillary carcinoma of the breastHISTOPATHOLOGY, Issue 6 2007A H S Lee Aim:, Metastases from ovarian serous papillary carcinoma to the breast and primary invasive micropapillary carcinoma of the breast are histologically similar. The distinction is clinically important to ensure appropriate management. Wilms' tumour-1 (WT1) and Ca125 are frequently expressed in serous papillary carcinomas, and uncommonly in unselected mammary carcinomas. One previous study found Ca125 expression in 69% of invasive micropapillary carcinomas. The aim was to assess the frequency of expression of WT1 and Ca125 in invasive micropapillary carcinoma. Methods and results:, Twenty-five of 34 invasive micropapillary carcinomas showed no nuclear expression of WT1. The remaining nine tumours showed weak to moderate immunoreactivity in 1,10% of nuclei. Six of these nine tumours also contained ductal carcinoma in situ, which expressed WT1 in five of the six. Membranous or cytoplasmic expression of Ca125 was found in seven tumours. Conclusion:, Nuclear WT1 expression is present in a minority of invasive micropapillary carcinomas and, when present, expression is focal. The frequency of expression of Ca125 was similar to the results in unselected mammary carcinoma. Thus, these markers are useful members of the immunohistochemical panel for the distinction of mammary invasive micropapillary carcinoma from ovarian serous papillary carcinoma. [source] Sustained delivery and efficacy of polymeric nanoparticles containing osteopontin and bone sialoprotein antisenses in rats with breast cancer bone metastasisINTERNATIONAL JOURNAL OF CANCER, Issue 7 2010Victoria Elazar Abstract Poor prognosis in mammary carcinoma is associated with a certain expression profile of a defined set of genes including osteopontin and bone sialoprotein. Efficient and specific delivery of antisenses (AS) and a protection of the sequences from degradation are the crucial conditions for AS therapeutic efficiency. We hypothesized that effective and safe AS delivery direceted against these genes could be achieved by polymeric nanoparticles (NP) fabricated from a biocompatible polymer. Due to their nano-size range and small negative charge, AS-NP can overcome the absorption barrier offering increased resistance to nuclease degradation, sustained duration of AS administration, and consequently, prolonged antisense action. The ASs designed against OPN and BSP-II were successfully encapsulated in NP composed of the biodegradable and biocompatible polylactide- co -glycolide polymer (PLGA), exhibiting sustained release and stability of the ASs. The therapeutic efficacy of the AS-NP delivery system was examined in vitro, and in a breast cancer bone metastasis animal model of MDA-MB-231 human breast cancer cells in nude rats. Treatment with OPN-AS or BSP-AS loaded NP in comparison with osmotic mini-pumps (locoregional injection and SC implants, respectively) resulted in a significant decrease in both, tumor bone metastasis incidence and in the size of the lesions in rats with metastases. Despite its smaller dose, AS-NP exhibited a better therapeutic efficacy than osmotic mini-pumps in terms of lesion ratio at later time periods (8,12 weeks). It may be concluded that AS delivery by NP is a promising therapeutic modality providing stability of the encapsulated AS and a sustained release. [source] Gene expression profiling during rat mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthraceneINTERNATIONAL JOURNAL OF CANCER, Issue 6 2009Masakazu Souda Abstract 7,12-Dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinoma is a well-recognized model; however, the genetic alterations during its carcinogenesis have yet to be determined. We used laser capture microdissection to specifically isolate cells from terminal end buds (TEBs), the origin of carcinoma, at 2 weeks after sesame oil treatment (control) or DMBA treatment (DMBA-TEBs), ductal carcinoma in situ (DCIS) and invasive mammary carcinoma (MC). Using an oligonucleotide microarray representing 20,600 rat probe sequences, we analyzed gene expression profiles and validated mRNA and protein levels of genes of interest byreal-time quantitative PCR and immunohistochemistry. The number of differentially expressed genes dramatically increased from DMBA-TEBs (63) to DCIS (798) and MC (981). Only the expression of PEP-19, an anti-apoptotic gene, showed significant increases in DMBA-TEBs (4-fold), DCIS (10-fold) and MC (16-fold). MMP-13 expression was increased markedly in DCIS (19-fold) and MC (61-fold) while OPN expression was increased 6-fold in DCIS and 8-fold in MC. MMP-7 expression was increased 4-fold in MC. Nidogen-1; a participant in the assembly of basement membranes, TSP-2; an inhibitor of angiogenesis and COUP-TFI; a transcription repressor showed significant decreases in DCIS (4-, 9- and 17-fold, respectively) and MC (10-, 37- and 100-fold). Network analyses with IPA software revealed that the most significant network included Akt groups in DCIS and ERK groups in MC. The present findings provide us with a better understanding of the molecular alteration that occur during mammary carcinogenesis and suggest the importance of PEP-19 overexpression in the very early stage of mammary carcinogenesis. © 2009 UICC [source] Detection of different tumor growth kinetics in single transgenic mice with oncogene-induced mammary carcinomas by flat-panel volume computed tomographyINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Katharina Jannasch Abstract Transgenic mouse models offer an excellent opportunity for studying the molecular basis of cancer development and progression. Here we applied flat-panel volume computed tomography (fpVCT) to monitor tumor progression as well as the development of tumor vasculature in vivo in a transgenic mouse model for oncogene-induced mammary carcinogenesis (WAP-T mice). WAP-T mice develop multiple mammary carcinomas on oncogene induction within 3 to 5 months. Following induction, 3-dimensional fpVCT data sets were obtained by serial single scans of entire mice in combination with iodine containing contrast agents and served as basis for precise measurements of tumor volumes. Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm3) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice. Furthermore, blood supply to the breast tumors, as well as blood vessels around and within the tumors, were clearly visible over time by fpVCT. Three-dimensional visualization of tumor vessels in high resolution was enhanced by the use of a novel blood pool contrast agent. Here, we demonstrate by longitudinal fpVCT imaging that mammary carcinomas develop at different time points in each WAP-T mouse, and thereafter show divergent growth rates and distinct vascularization patterns. © 2009 UICC [source] Increased antitumor potential of the raloxifene prodrug, raloxifene diphosphateINTERNATIONAL JOURNAL OF CANCER, Issue 9 2008Yoshinori Okamoto Abstract Raloxifene (RAL) significantly reduced the incidence of breast cancer in women at high risk of developing the disease. Unlike tamoxifen (TAM), an increased incidence of endometrial cancer was not observed in women treated with RAL. However, RAL, having two hydroxyl moieties, can be conjugated rapidly through phase II metabolism and excreted, making it difficult to achieve adequate bioavailability by oral administration in humans. As a result, higher doses must be administered to obtain an efficacy equivalent to that achieved with TAM. To improve oral bioavailability and antitumor potential, RAL diphosphate was prepared as a prodrug. RAL diphosphate showed several orders of magnitude lower binding potential to both ER, and ER, and weak antiproliferative potency on cultured human MCF-7 and ZR-75-1 breast cancer cells, as compared to RAL. However, RAL diphosphate has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL against both 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats and human MCF-7 breast cancer implanted in athymic nude mice. The RAL prodrug may provide greater clinical benefit for breast cancer therapy and prevention. © 2008 Wiley-Liss, Inc. [source] Epithelioid angiosarcoma of the breast involving the skin: a highly aggressive neoplasm readily mistaken for mammary carcinomaJOURNAL OF CUTANEOUS PATHOLOGY, Issue 2 2003M. C. Fariña Background: Angiosarcomas are malignant neoplasms of endothelial cells. Angiosarcoma of the breast is a rare neoplasm that behaves in a highly malignant fashion. It must be differentiated from benign vascular proliferations and from mammary carcinoma. Methods: We report on a 49-year-old-woman who presented with a large mass involving the left breast. Results: The lesion had an erythematoviolaceous hue and livedoid pattern at the periphery. Histopathologic study showed an epithelioid malignant neoplasm, and immunohistochemical studies demonstrated that neoplastic cells expressed immunoreactivity for endothelial cell markers. Conclusions: A diagnosis of epithelioid angiosarcoma of the breast was established. The patient was treated with radical mastectomy, but she refused any other additional therapy. [source] Sentinel lymph node as a new marker for therapeutic planning in breast cancer patientsJOURNAL OF SURGICAL ONCOLOGY, Issue 3 2004Marco Gipponi MD Abstract Background and Objectives Literature review suggests that the sentinel lymph node (sN) represents a reliable predictor of axillary lymph node status in breast cancer patients; however, some important issues, such as the optimisation of the technique for the intraoperative identification of the sN, the role of intraoperative frozen section examination of the sN, and the clinical implications of sN metastasis as regards the surgical management of the axilla, still require further confirmation. The authors aimed (1) to assess the feasibility of sN identification with a combined approach (vital blue dye lymphatic mapping and radioguided surgery, RGS) and the specific contribution of either techniques to the detection of the sN, (2) to determine the accuracy and usefulness of intraoperative frozen section examination of the sN in order to perform a one-stage surgical procedure, and (3) to define how the sN might modulate the therapeutic planning in different stages of disease. Materials and Methods From October 1997 to June 2001, 334 patients with early-stage (T1,2 N0 M0) invasive mammary carcinoma underwent sN biopsy; the average age of patients was 61.5 years (range, 39,75 years). In a subset of 153 patients, both vital blue dye (Patent Blue-V) lymphatic mapping and RGS were used to identify the sN, and the relative contribution of each of the two techniques was assessed. Results In the whole group, the sN was identified in 326 of 334 patients (97.6%), and 105 of 326 patients (37.3%) had positive axillary lymph nodes (pN+). In 9 of 105 pN+ patients, the definitive histologic examination of the sN did not show metastases but these were detected in non-sN, thus giving an 8.6% false-negative rate, a negative predictive value of 94.5% (156/165), and an accuracy of 96.5% (252/261). As regards the specific contribution of the two different techniques used in the identification of the sN, the detection rate was 73.8% (113/153) with Patent Blue-V alone, 94.1% (144/153) with RGS alone, and 98.7% (151/153) with Patent Blue-V combined with RGS (P,<,0.001). Noteworthy, whenever the sN was identified, the prediction of axillary lymph node status was remarkably similar (93,95% sensitivity; 100% specificity; 95,97% negative predictive value, and 97,98% accuracy) whichever of the three procedures was adopted (Patent Blue-V alone, RGS alone, or combined Patent Blue-V and RGS). Intraoperative frozen section examination was performed in 261 patients, who had at least one sN identified, out of 267 patients who underwent complete axillary dissection; 170 patients had histologically negative sN (i.o. sN,) and 91 patients histologically positive sN (i.o. sN+). All 91 i.o. sN+ were confirmed by definitive histology, whereas in 14 of 170 i.o. sN, patients (8.2%) metastases were detected at definitive histology. As regards the correlation between the size of sN metastasis, the primary tumour size, and the status of non-sN in the axilla, micrometastases were detected at final histology in 23 patients and macrometastases in 82 patients. When only micrometastases were detected, the sN was the exclusive site of nodal metastasis in 20 of 23 patients (86.9%) while in 3 patients with tumour size larger than 10 mm micrometastases were detected also in non-sN. Macrometastases were never detected in pT1a breast cancer patients; the sN was the exclusive site of these metastases in 30 patients (36.6%), while in 52 patients (63.4%) there were metastases both in sN and non-sN. Conclusions Sentinel lymphadenectomy can better be accomplished when both procedures (lymphatic mapping with vital blue dye and RGS) are used, because of the significantly higher sN detection rate, although the prediction of axillary lymph node status remains remarkably similar whichever method is used. The intraoperative frozen section examination proved to be rather accurate in predicting the actual pathologic status of the sN, with a negative predictive value of 91.8%; in 35% of patients it allowed sN biopsy and axillary dissection to be performed in a one-stage surgical procedure. Finally, specific clinical and histopathologic features of the primary tumour and sN might be used to tailor the loco-regional and systemic treatment in different clinical settings, such as in ductal carcinoma in-situ (DCIS), early-stage invasive breast cancer, and patients with large breast cancer undergoing neo-adjuvant CT for breast-saving surgery as well as elderly patients with operable breast cancer. J. Surg. Oncol. 2004;85:102,111. © 2004 Wiley-Liss, Inc. [source] Recuperative effect of Semecarpus anacardium linn. nut milk extract on carbohydrate metabolizing enzymes in experimental mammary carcinoma-bearing ratsPHYTOTHERAPY RESEARCH, Issue S1 2002Venugopal Sujatha Abstract Semecarpus anacardium Linn. of the family Anacardiaceae has many applications in the Ayurvedic and Siddha systems of medicine. We have tested the antitumour activity of Semecarpus anacardium nut extract against experimental mammary carcinoma in animals. As there is a direct relationship between the proliferation of tumour cells and the activities of the glycolytic and gluconeogenic enzymes, we studied changes in the activities of enzymes involved in this metabolic pathway in the liver and kidney. The enzymes investigated were glycolytic enzymes, namely hexokinase, phosphoglucoisomerase, aldolase and the gluconeogenic enzymes, namely glucose-6-phosphatase and fructose-1,6-biphosphatase in experimental rats. A significant rise in glycolytic enzyme activities and a simultaneous fall in gluconeogenic enzyme activities were found in mammary carcinoma bearing rats. Drug administration returned these enzyme activities to their respective control activities. Copyright © 2002 John Wiley & Sons, Ltd. [source] Invasive neuroendocrine carcinoma of the breastCANCER, Issue 19 2010A distinctive subtype of aggressive mammary carcinoma Abstract BACKGROUND: Neuroendocrine carcinoma (NEC) of the breast, a pathologic entity newly defined in the 2003 World Health Organization classification of tumors, is a rare type of tumor that is not well recognized or studied. The purpose of this first case-controlled study is to reveal the clinicopathologic features, therapeutic response, and outcomes of patients with NEC of the breast. METHODS: Seventy-four patients with NEC of the breast who were treated at The University of Texas M. D. Anderson Cancer Center were analyzed; 68 of them had complete clinical follow-up. Two cohorts of invasive mammary carcinoma cases were selected to pair with NEC to reveal demographic, pathologic, and clinical features at presentation, along with therapeutic response to treatment and patient outcomes. RESULTS: NEC was more likely to be estrogen receptor/progesterone receptor positive and human epidermal growth factor receptor 2 negative. Despite similar age and disease stages at presentation, NEC showed a more aggressive course than invasive ductal carcinoma, with a higher propensity for local and distant recurrence and poorer overall survival. High nuclear grade, large tumor size, and regional lymph node metastasis were significant negative prognostic factors for distant recurrence-free survival; high nuclear grade and regional lymph node metastasis were also significant negative prognostic factors for overall survival. Although endocrine therapy and radiation therapy showed a trend toward improved survival, the small number of cases in this study limited the statistical power to reveal therapeutic benefits in NEC of the breast. CONCLUSIONS: NEC is a distinct type of aggressive mammary carcinoma. Novel therapeutic approaches should be explored for this uniquely different clinical entity. Cancer 2010. © 2010 American Cancer Society. [source] Ductal lavage in patients undergoing mastectomy for mammary carcinomaCANCER, Issue 10 2003A correlative study Abstract BACKGROUND Ductal lavage (DL) is a new method for the sampling of breast epithelium. Data regarding its sensitivity in the detection of epithelial abnormalities, including carcinoma in situ (CIS), remains limited. METHODS DL was performed in the affected breasts of 26 women undergoing mastectomy for mammary carcinoma and in the clinically normal breast of 4 additional women undergoing risk-reducing mastectomy. After surgery, dye was injected through the microcatheter used for DL. Three cytopathologists independently reviewed all DL slides and the data reflect consensus by at least two reviewers. Interobserver agreement was assessed. The findings in DL samples were correlated with the features of CIS in the mastectomy specimens. RESULTS Four (14%) of 29 DL samples satisfactory for evaluation showed marked atypia, 10 (34%) showed mild atypia, and 15 (52%) were benign. No DL sample was clearly malignant. Interobserver agreement was good (average kappa = 0.52). Of the DL samples satisfactory for evaluation, 27 had been obtained from 24 breasts containing CIS, which included 18 ductal CIS (DCIS), 3 lobular CIS (LCIS), 2 DCIS and LCIS, and 1 solid CIS with mixed ductal and lobular features. Invasive carcinoma was present in 20 samples. Two DL samples from breasts with extensive LCIS showed mild atypia and injected dye was identified in ducts and lobules involved by LCIS. CONCLUSIONS DL had low sensitivity for CIS in breasts that also contained invasive carcinoma. The use of DL remains investigational, and close follow-up should be continued for all patients undergoing DL, including those with benign diagnoses. Cancer 2003. © 2003 American Cancer Society. [source] Up-regulation of pro-inflammatory genes as adaptation to hypoxia in MCF-7 cells and in human mammary invasive carcinoma microenvironmentCANCER SCIENCE, Issue 4 2010Marco Tafani The role of tumor cells in synthesizing pro-inflammatory molecules is still controversial. Here we report that hypoxic treatment of the MCF-7 human mammary adenocarcinoma cell line induced activation of hypoxia-inducible factor 1, (HIF-1,) and nuclear factor-kappa B (NF-,B). Importantly, hypoxia regulated expression of alarmin receptors such as the receptor for advanced glycation end products (RAGE) and the purinoreceptor (P2X7R), and up-regulated inflammatory response (IR) genes such as the inducible enzymes nitric oxide synthase (NOS2), cycloxygenase (COX2), and the acute-phase protein pentraxin-3 (PTX3). Hypoxia also stimulated chemokine (C-X-C motif) receptor 4 (CXCR4) mRNA synthesis. In fact, the CXCR4 ligand stromal-derived factor-1, (SDF-1,) increased invasion and migration of hypoxic MCF-7 cells. Inhibition of HIF-1, by chetomin and NF-,B by parthenolide reduced mRNA and protein expression of the studied molecules and prevented invasion of hypoxic MCF-7 cells. Moreover, solid invasive mammary tumor microenvironment was analyzed after laser-capture microdissection (LCMD) comparing tumor versus host normal tissue. Nuclear translocation of HIF-1, and NF-,B and up-regulation of IR, CXCR4, estrogen receptor , (ER,), and epithelial growth factor receptor (EGFR) was observed in tumor but not in host normal tissue in the absence of a local inflammatory leukocyte infiltrate. We conclude that under hypoxic conditions MCF-7 cells acquire a pro-inflammatory phenotype, and that solid human mammary carcinoma evidenced a similar activation of HIF-1,, NF-,B, and IR genes in malignant tumor cells as compared to the normal host tissues. We suggest a role for IR activation in the malignant progression of transformed cells. (Cancer Sci 2010; 101: 1014,1023) [source] Metastatic mammary carcinomas with endocrine features: Potential diagnostic pitfallsDIAGNOSTIC CYTOPATHOLOGY, Issue 1 2005Anjali Saqi M.D. Abstract Mammary carcinomas with endocrine differentiation (MCED) are an uncommon subtype of breast carcinomas that are morphologically indistinguishable from low-grade endocrine neoplasms arising in other organs. Aspirates of MCED yield relatively monotonous cells with eccentrically placed nuclei containing characteristic "salt and pepper" chromatin. In the breast, these features represent MCED. In extramammary sites, the differential is more extensive, and diagnosing MCED metastates to the lung, a common location for primary and metastatic endocrine tumors, can be a challenging task, with significant clinical implications. Although primary MCED have been described extensively in the cytology literature, secondary pulmonary MCED have not been reported to the best of our knowledge. We report three cases of MCED metastatic to the lung and present the cytological and immunohistochemical features. Diagn. Cytopathol. 2005;33:49,53. © 2005 Wiley-Liss, Inc. [source] The expression of Wilms' tumour-1 and Ca125 in invasive micropapillary carcinoma of the breastHISTOPATHOLOGY, Issue 6 2007A H S Lee Aim:, Metastases from ovarian serous papillary carcinoma to the breast and primary invasive micropapillary carcinoma of the breast are histologically similar. The distinction is clinically important to ensure appropriate management. Wilms' tumour-1 (WT1) and Ca125 are frequently expressed in serous papillary carcinomas, and uncommonly in unselected mammary carcinomas. One previous study found Ca125 expression in 69% of invasive micropapillary carcinomas. The aim was to assess the frequency of expression of WT1 and Ca125 in invasive micropapillary carcinoma. Methods and results:, Twenty-five of 34 invasive micropapillary carcinomas showed no nuclear expression of WT1. The remaining nine tumours showed weak to moderate immunoreactivity in 1,10% of nuclei. Six of these nine tumours also contained ductal carcinoma in situ, which expressed WT1 in five of the six. Membranous or cytoplasmic expression of Ca125 was found in seven tumours. Conclusion:, Nuclear WT1 expression is present in a minority of invasive micropapillary carcinomas and, when present, expression is focal. The frequency of expression of Ca125 was similar to the results in unselected mammary carcinoma. Thus, these markers are useful members of the immunohistochemical panel for the distinction of mammary invasive micropapillary carcinoma from ovarian serous papillary carcinoma. [source] Detection of different tumor growth kinetics in single transgenic mice with oncogene-induced mammary carcinomas by flat-panel volume computed tomographyINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Katharina Jannasch Abstract Transgenic mouse models offer an excellent opportunity for studying the molecular basis of cancer development and progression. Here we applied flat-panel volume computed tomography (fpVCT) to monitor tumor progression as well as the development of tumor vasculature in vivo in a transgenic mouse model for oncogene-induced mammary carcinogenesis (WAP-T mice). WAP-T mice develop multiple mammary carcinomas on oncogene induction within 3 to 5 months. Following induction, 3-dimensional fpVCT data sets were obtained by serial single scans of entire mice in combination with iodine containing contrast agents and served as basis for precise measurements of tumor volumes. Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm3) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice. Furthermore, blood supply to the breast tumors, as well as blood vessels around and within the tumors, were clearly visible over time by fpVCT. Three-dimensional visualization of tumor vessels in high resolution was enhanced by the use of a novel blood pool contrast agent. Here, we demonstrate by longitudinal fpVCT imaging that mammary carcinomas develop at different time points in each WAP-T mouse, and thereafter show divergent growth rates and distinct vascularization patterns. © 2009 UICC [source] Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumorsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Christopher M. Heaphy Abstract Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of "field cancerization" and "cancer field effect," concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery. © 2006 Wiley-Liss, Inc. [source] Oxytocin and Oxytocin Receptors in Cancer Cells and ProliferationJOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2004P. Cassoni Abstract The hypothalamic nonapeptide oxytocin plays a crucial role in many reproductive and behavioural functions. However, in recent years, an additional new role for oxytocin has been identified in neoplastic pathology. In tumours, oxytocin acts as a growth regulator, through the activation of a specific G-coupled transmembrane receptor, the oxytocin receptor. In vitro, oxytocin inhibits proliferation of neoplastic cells of either epithelial (mammary and endometrial), nervous or bone origin, all expressing oxytocin receptor. Furthermore, an oxytocin growth-inhibiting effect was also tested and confirmed in vivo in mouse and rat mammary carcinomas. In neoplastic cells derived from two additional oxytocin target tissues, trophoblast and endothelium, oxytocin was found to promote cell proliferation, an effect opposite to that previously described in all other neoplastic oxytocin-responsive cells. The signal transduction pathways coupled to the biological effects of oxytocin are different in oxytocin growth-inhibited or growth-stimulated cells, and may depend on the membrane localization of the oxytocin receptor itself. The inhibitory effect of oxytocin is apparently mediated by activation of the cAMP-protein kinase A pathway, a nonconventional oxytocin signalling pathway, whereas the mitogenic effect is coupled to the increase of intracellular [Ca2+] and tyrosine phosphorylation, ,classical' oxytocin transducers. Moreover, the oxytocin receptor localization in lipid rafts enriched in caveolin-1 turns the inhibition of cell growth into a proliferative response, eliciting different epidermal growth factor receptor/mitogen-activated protein kinase activation patterns. This unexpected role of oxytocin (and oxytocin analogues) in regulating cell proliferation, as well as the widespread expression of oxytocin receptors in neoplastic tissues of different origin, opens up new perspectives on the biological role of the oxytocin,oxytocin receptor system in cancer. [source] Identification of key residues involved in mediating the in vivo anti-tumor/anti-endothelial activity of AlphastatinJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2007C. A. STATON Summary., Background :,We have recently shown that Alphastatin, a 24-amino-acid peptide (ADSGEGDFLAEGGGVRGPRVVERH) derived from human fibrinogen has anti-endothelial properties in vitro and in vivo. Objectives:, The aim of this study was to determine the activity of a terminally modified (stabilized) form of Alphastatin in vitro and in vivo and to identify the key residues required for this activity. Methods:, The in vitro activity of modified Alphastatin, truncates and mutants was determined by endothelial cell (HuDMEC) tubule formation and migration. Active peptides were then assessed in vivo using syngeneic murine subcutaneous 4T1 mammary carcinomas. Results:, Modified Alphastatin-inhibited HuDMEC migration and tubule formation in response to multiple growth factors and caused a 45% inhibition in tumor growth when administered intravenously at 0.25 mg kg,1 (three times per week). Intravenous (i.v.) administration proved non-toxic at all doses investigated, whereas oral and intraperitoneal (i.p.) administration demonstrated neither anti-tumor activity nor toxicity. Truncations of Alphastatin revealed an 11-amino-acid peptide (DFLAEGGGVRG), termed AHN419, which inhibited endothelial cell activity in vitro; however, intravenous AHN419 caused a non-significant growth inhibition in vivo. Single amino acid substitutions to alanine along the entire length of Alphastatin indicated that additional residues outside the AHN419 sequence were required for full activity. Conclusions:, Terminal modification of Alphastatin altered the in vivo efficacy and these studies suggest that a hydrophobic cluster (Phe8, Leu9, Ala10 and Val15) is essential for the biological activity, but additional residues, including Ser3-Gly14, Pro18-Val20 and Arg23 are required for full inhibitory activity of Alphastatin. [source] Increasing the efficiency of photodynamic therapy by improved light delivery and oxygen supply using an anticoagulant in a solid tumor modelLASERS IN SURGERY AND MEDICINE, Issue 7 2010Liyong Yang MS Abstract Background and Objective The main factors in photodynamic therapy (PDT) are: photosensitizer retention, photon absorption, and oxygen supply. Each factor has its unique set of problems that poses limitation to the treatment. Both light delivery and oxygen supply are significant bottlenecks in PDT. Vascular closure during PDT reduces oxygen supply to the targeted tissue. On the other hand, with the changes in blood perfusion, the tissue optical properties change, and result in variation in irradiation light transmission. For these reasons, it becomes very important to avoid blood coagulation and vascular closure during PDT. Study Design/Materials and Methods The efficiency of PDT combined with the anticoagulant heparin was studied in a BALB/c mouse model with subcutaneous EMT6 mammary carcinomas. Mice were randomized into three groups: control, PDT-only, and PDT with heparin. The photosensitizer Photofrin® was used in our experiments. Light transmission, blood perfusion, and local production of reactive oxygen species (ROS) were monitored during the treatment. The corresponding histological examinations were performed to determine the thrombosis immediately after irradiation and to evaluate tumor necrosis 48,hours after the treatment. Results The results clearly demonstrated that PDT combined with pre-administered heparin can significantly reduce thrombosis during light irradiation. The blood perfusion, oxygen supply, and light delivery are all improved. Improved tumor responses in the combined therapy, as shown with the histological examination and tumor growth assay, are clearly demonstrated and related to an increased local ROS production. Conclusion Transitory anticoagulation treatment significantly enhances the antitumor effect of PDT. It is mainly due to the improvement of the light delivery and oxygen supply in tumor, and ultimately the amount of ROS produced during PDT. Lasers Surg. Med. 42:671,679, 2010. © 2010 Wiley-Liss, Inc. [source] Characterisation of ligand binding to the parathyroid hormone/parathyroid hormone-related peptide receptor in MCF7 breast cancer cells and SaOS-2 osteosarcoma cellsCELL BIOCHEMISTRY AND FUNCTION, Issue 2 2007Majed S. Alokail Abstract Parathyroid hormone-related peptide (PTHrP) and parathyroid hormone (PTH)/PTHrP-receptor, PTH/PTHrP-R, are frequently expressed in mammary carcinomas as well as in bone cells. In this study we compared the ligand binding characteristics of the PTH/PTHrP,R in SaOS-2 human osteosarcoma cells with those in MCF7 breast cancer cells. We used both Scatchard analysis of saturation kinetics for iodinated ligand and the level of expressed receptor protein by visualising the single radio-labelled receptor-ligand complex from isolated membrane preparations from the two cell lines. In MCF7 cells, ligand binding, (receptor number) was increased by prior exposure of the cultured cells to epidermal growth factor (EGF), estradiol (E2), or dexamethasone (DEX), and decreased following calcitriol (1,25 DHCC). In contrast in the SaOS-2 cells, PTH/PTHrP-R number was increased by exposure to E2 and 1,25DHCC and decreased by DEX while EGF had no effect. These data were confirmed when the PTH/PTHrP-R was cross linked with 125I-PTHrP-1-34Tyr, and extended by visualising the intensity of the isolated radiolabelled receptor complex by autoradiography following SDS-PAGE at several time points during the treatment. Copyright © 2005 John Wiley & Sons, Ltd. [source] | |||||||||||||||||||||||||