Aberrant RET expression affects normal mammary gland post-lactation transition, enhancing cancer potential.

RET is a receptor tyrosine kinase with oncogenic potential in the mammary epithelium. Several receptors with oncogenic activity in the breast are known to participate in specific developmental stages. We found that RET is differentially expressed during mouse mammary gland development: RET is present in lactation and its expression dramatically decreases in involution, the period during which the lactating gland returns to a quiescent state after weaning. Based on epidemiological and pre-clinical findings, involution has been described as tumor promoting. Using the Ret/MTB doxycycline-inducible mouse transgenic system, we show that sustained expression of RET in the mammary epithelium during the post-lactation transition to involution is accompanied by alterations in tissue remodeling and an enhancement of cancer potential. Following constitutive Ret expression, we observed a significant increase in neoplastic lesions in the post-involuting versus the virgin mammary gland. Furthermore, we show that abnormal RET overexpression during lactation promotes factors that prime involution, including premature activation of Stat3 signaling and, using RNA sequencing, an acute-phase inflammatory signature. Our results demonstrate that RET overexpression negatively affects the normal post-lactation transition.

Heme Oxygenase 1 Impairs Glucocorticoid Receptor Activity in Prostate Cancer.

Glucocorticoids are used during prostate cancer (PCa) treatment. However, they may also have the potential to drive castration resistant prostate cancer (CRPC) growth via the glucocorticoid receptor (GR). Given the association between inflammation and PCa, and the anti-inflammatory role of heme oxygenase 1 (HO-1), we aimed at identifying the molecular processes governed by the interaction between HO-1 and GR. PCa-derived cell lines were treated with Hemin, Dexamethasone (Dex), or both. We studied GR gene expression by RTqPCR, protein expression by Western Blot, transcriptional activity using reporter assays, and nuclear translocation by confocal microscopy. We also evaluated the expression of HO-1, FKBP51, and FKBP52 by Western Blot. Hemin pre-treatment reduced Dex-induced GR activity in PC3 cells. Protein levels of FKBP51, a cytoplasmic GR-binding immunophilin, were significantly increased in Hemin+Dex treated cells, possibly accounting for lower GR activity. We also evaluated these treatments in vivo using PC3 tumors growing as xenografts. We found non-significant differences in tumor growth among treatments. Immunohistochemistry analyses revealed strong nuclear GR staining in almost all groups. We did not observe HO-1 staining in tumor cells, but high HO-1 reactivity was detected in tumor infiltrating macrophages. Our results suggest an association and crossed modulation between HO-1 and GR pathways.

R-spondin3 Is Associated with Basal-Progenitor Behavior in Normal and Tumor Mammary Cells.

R-spondin3 (RSPO3) is a member of a family of secreted proteins that enhance Wnt signaling pathways in diverse processes, including cancer. However, the role of RSPO3 in mammary gland and breast cancer development remains unclear. In this study, we show that RSPO3 is expressed in the basal stem cell-enriched compartment of normal mouse mammary glands but is absent from committed mature luminal cells in which exogenous RSPO3 impairs lactogenic differentiation. RSPO3 knockdown in basal-like mouse mammary tumor cells reduced canonical Wnt signaling, epithelial-to-mesenchymal transition-like features, migration capacity, and tumor formation in vivo Conversely, RSPO3 overexpression, which was associated with some LGR and RUNX factors, highly correlated with the basal-like subtype among patients with breast cancer. Thus, we identified RSPO3 as a novel key modulator of breast cancer development and a potential target for treatment of basal-like breast cancers.Significance: These findings identify RSPO3 as a potential therapetuic target in basal-like breast cancers.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4497/F1.large.jpg Cancer Res; 78(16); 4497-511. ©2018 AACR.

Expression of the mRNA stability regulator Tristetraprolin is required for lactation maintenance in the mouse mammary gland.

Tristetraprolin (TTP), an mRNA-binding protein that negatively controls levels of inflammatory factors, is highly expressed in the lactating mouse mammary gland. To determine the biological relevance of this expression profile, we developed bi-transgenic mice in which this protein is specifically down-regulated in the secretory mammary epithelium in the secretory mammary epithelium during lactation. Our data show that TTP conditional KO mice produced underweight litters, possibly due to massive mammary cell death induced during lactation without the requirement of additional stimuli. This effect was linked to overexpression of inflammatory cytokines, activation of STAT3 and down-regulation of AKT phosphorylation. Importantly, blocking TNFα activity in the lactating conditional TTP KO mice inhibited cell death and similar effects were observed when this treatment was applied to wild-type animals during 48 h after weaning. Therefore, our results demonstrate that during lactation TTP wards off early involution by preventing the increase of local inflammatory factors. In addition, our data reveal the relevance of locally secreted TNFα for triggering programmed cell death after weaning.

Improvement of Antitumor Therapies Based on Vaccines and Immune-Checkpoint Inhibitors by Counteracting Tumor-Immunostimulation.

Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.

Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis.

An abrupt increase in metastatic growth as a consequence of the removal of primary tumors suggests that the concomitant resistance (CR) phenomenon might occur in human cancer. CR occurs in murine tumors and ROS-damaged phenylalanine, meta-tyrosine (m-Tyr), was proposed as the serum anti-tumor factor primarily responsible for CR. Herein, we demonstrate for the first time that CR happens in different experimental human solid tumors (prostate, lung anaplastic, and nasopharyngeal carcinoma). Moreover, m-Tyr was detected in the serum of mice bearing prostate cancer (PCa) xenografts. Primary tumor growth was inhibited in animals injected with m-Tyr. Further, the CR phenomenon was reversed when secondary implants were injected into mice with phenylalanine (Phe), a protective amino acid highly present in primary tumors. PCa cells exposed to m-Tyr in vitro showed reduced cell viability, downregulated NFκB/STAT3/Notch axis, and induced autophagy; effects reversed by Phe. Strikingly, m-Tyr administration also impaired both, spontaneous metastasis derived from murine mammary carcinomas (4T1, C7HI, and LMM3) and PCa experimental metastases. Altogether, our findings propose m-Tyr delivery as a novel approach to boost the therapeutic efficacy of the current treatment for metastasis preventing the escape from tumor dormancy.

An optimised protocol for platelet-rich plasma preparation to improve its angiogenic and regenerative properties.

Although platelet-rich plasma (PRP) is used as a source of growth factors in regenerative medicine, its effectiveness remains controversial, partially due to the absence of PRP preparation protocols based on the regenerative role of platelets. Here, we aimed to optimise the protocol by analysing PRP angiogenic and regenerative properties. Three optimising strategies were evaluated: dilution, 4 °C pre-incubation, and plasma cryoprecipitate supplementation. Following coagulation, PRP releasates (PRPr) were used to induce angiogenesis in vitro (HMEC-1 proliferation, migration, and tubule formation) and in vivo (chorioallantoic membrane), as well as regeneration of excisional wounds on mouse skin. Washed platelet releasates induced greater angiogenesis than PRPr due to the anti-angiogenic effect of plasma, which was decreased by diluting PRPr with saline. Angiogenesis was also improved by both PRP pre-incubation at 4 °C and cryoprecipitate supplementation. A combination of optimising variables exerted an additive effect, thereby increasing the angiogenic activity of PRPr from healthy donors and diabetic patients. Optimised PRPr induced faster and more efficient mouse skin wound repair compared to that induced by non-optimised PRPr. Acetylsalicylic acid inhibited angiogenesis and tissue regeneration mediated by PRPr; this inhibition was reversed following optimisation. Our findings indicate that PRP pre-incubation at 4 °C, PRPr dilution, and cryoprecipitate supplementation improve the angiogenic and regenerative properties of PRP compared to the obtained by current methods.

In Vivo Hemin Conditioning Targets the Vascular and Immunologic Compartments and Restrains Prostate Tumor Development.

Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study, we assessed how hemin, a pharmacologic inducer of heme oxygenase-1 (HO-1), has an impact on prostate cancer development in an in vivo conditioning model.Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays were performed to evaluate hemin effect on both angiogenesis and the immune response. To gain clinical insight, we used prostate cancer patient-derived samples in our studies to assess the expression of HO-1 and other relevant genes.Results: Conditioning resulted in increased tumor latency and decreased initial growth rate. Histologic analysis of tumors grown in conditioned mice revealed impaired vascularization. Hemin-treated human umbilical vein endothelial cells (HUVEC) exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1-conditioned media. Subcutaneous hemin conditioning hindered tumor-associated neovascularization in an in vivo Matrigel plug assay. In addition, hemin boosted CD8+ T-cell proliferation and degranulation in vitro and antigen-specific cytotoxicity in vivo A significant systemic increase in CD8+ T-cell frequency was observed in preconditioned tumor-bearing mice. Tumors from hemin-conditioned mice showed reduced expression of galectin-1 (Gal-1), key modulator of tumor angiogenesis and immunity, evidencing persistent remodeling of the microenvironment. We also found a subset of prostate cancer patient-derived xenografts and prostate cancer patient samples with mild HO-1 and low Gal-1 expression levels.Conclusions: These results highlight a novel function of a human-used drug as a means of boosting the antitumor response. Clin Cancer Res; 23(17); 5135-48. ©2017 AACR.

Base de datos sistematizada de historias clínicas pertenecientes al I. I. HEMA: informe preliminar / Systematized database of medical records belonging to I. I. HEMA: preliminary report

Se procedió a confeccionar una base de datos de los casos atendidos en Clínica Hematológica del Instituto de Investigaciones Hematológicas. Se registró información sobre: a) Datos demográficos; b) Enfermedad actual; c) Métodos diagnósticos y d) Clasificación de las enfermedades según CIE 10. Sobre un total de 3573 casos registrados entre junio de 2002 y noviembre 2015 se analizaron 1300 (42%) casos. Los principales resultados muestran un predominio de las anemias, y entre ellas las ferropénicas. El mielograma y el frotis de sangre periférica predominaron entre los procedimientos diagnósticos. El tiempo entre primera consulta y diagnóstico muestra que en la mayoría (79,24%) de los casos este fue menor a 3 meses. En un 55,9 % de los casos se inició tratamiento antes del mes. (AU)

A data base was made from cases treated in the Hematological Clinic service. The following information was recorded: a) Demographics; b) Current disease; c) Diagnostic methods and d) Disease classification according to CIE 10. There were analyzed 1300 (42%) out of 3573 cases between June 2002 and November 2015. The main results show predominance of anemia and among them iron deficiency. The myelogram and peripheral blood smear predominated among the diagnostic procedures. Time between first consultation and diagnosis shows that in the majority (79.24%) of cases was less than 3 months. In 55.9% of cases it started treatment before the month. (AU)

Meta-tyrosine. A powerful anti-metastatic factor with undetectable toxic-side effects.

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.

Meta-tyrosine: A powerful anti-metastatic factor with undetectable toxic-side effects

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.(AU)

La resistencia concomitante antitumoral (RC) es el fenómeno según el cual un individuo portador de tumor inhibe el crecimiento de implantes tumorales secundarios y metástasis. Si bien desde hace tiempo se sabe que la RC inducida por tumores inmunogénicos de pequeño tamaño es generada por mecanismos inmunológicos dependientes de células T, por otro lado, la manifestación más universal de la RC, generada tanto por tumores inmunogénicos como no-inmunogénicos de gran tamaño, había sido asociada con un (unos) factor sérico antitumoral cuya naturaleza permaneció elusiva por años. En un trabajo reciente, nuestro grupo de trabajo identificó este factor como la mezcla equi-molar de meta-tirosina y orto-tirosina, dos isómeros de tirosina que no están presentes en proteínas normales y que demostraron ser responsables del 90% y 10%, respectivamente, de la actividad antitumoral total del suero. En este trabajo, continuamos nuestras investigaciones demostrando que la administración periódica de meta-tirosina reducía drásticamente el número de metástasis pulmonares y hepáticas en ratones portadores de dos tumores murinos altamente metastásicos y disminuía dramáticamente la mortandad (de 100% a 25%) de ratones con metástasis ya establecidas al momento de la extirpación quirúrgica del tumor. Estos efectos anti-metastásicos se lograron aun con muy bajas concentraciones de meta-tirosina y sin efectos tóxicos perceptibles, lo que sugiere que su uso puede ayudar a diseñar nuevas y menos nocivas estrategias para el tratamiento del cáncer, especialmente aquellas destinadas a controlar el crecimiento metastásico, que es el problema más grave en la enfermedad oncológica.(AU)

Meta-tyrosine: A powerful anti-metastatic factor with undetectable toxic-side effects

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.

La resistencia concomitante antitumoral (RC) es el fenómeno según el cual un individuo portador de tumor inhibe el crecimiento de implantes tumorales secundarios y metástasis. Si bien desde hace tiempo se sabe que la RC inducida por tumores inmunogénicos de pequeño tamaño es generada por mecanismos inmunológicos dependientes de células T, por otro lado, la manifestación más universal de la RC, generada tanto por tumores inmunogénicos como no-inmunogénicos de gran tamaño, había sido asociada con un (unos) factor sérico antitumoral cuya naturaleza permaneció elusiva por años. En un trabajo reciente, nuestro grupo de trabajo identificó este factor como la mezcla equi-molar de meta-tirosina y orto-tirosina, dos isómeros de tirosina que no están presentes en proteínas normales y que demostraron ser responsables del 90% y 10%, respectivamente, de la actividad antitumoral total del suero. En este trabajo, continuamos nuestras investigaciones demostrando que la administración periódica de meta-tirosina reducía drásticamente el número de metástasis pulmonares y hepáticas en ratones portadores de dos tumores murinos altamente metastásicos y disminuía dramáticamente la mortandad (de 100% a 25%) de ratones con metástasis ya establecidas al momento de la extirpación quirúrgica del tumor. Estos efectos anti-metastásicos se lograron aun con muy bajas concentraciones de meta-tirosina y sin efectos tóxicos perceptibles, lo que sugiere que su uso puede ayudar a diseñar nuevas y menos nocivas estrategias para el tratamiento del cáncer, especialmente aquellas destinadas a controlar el crecimiento metastásico, que es el problema más grave en la enfermedad oncológica.

Concomitant tumor resistance.

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants. This phenomenon has been described in human and animal systems and it can be generated by both immunogenic and non-immunogenic tumors. The relevance of CR to the mechanisms of metastases control has been highlighted by numerous observations showing that the removal of human and murine tumors may be followed by an abrupt increase in metastatic growth, suggesting that a primary tumor may exert a controlling action on its metastases which could be considered as secondary tumor implants developed spontaneously during the primary tumor growth. A more profound understanding of the different mechanisms claimed to be associated with the phenomenon of CR could contribute to develop new and more harmless means to manage malignant diseases, especially by limiting the development of metastases that arise after resection of primary tumors or after other stressors that may promote the escape of metastases from dormancy.

Concomitant tumor resistance: the role of tyrosine isomers in the mechanisms of metastases control.

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. Although previous studies indicated that T-cell-dependent processes mediate CR in hosts bearing immunogenic small tumors, manifestations of CR induced by immunogenic and nonimmunogenic large tumors have been associated with an elusive serum factor. In a recently published study, we identified this factor as meta-tyrosine and ortho-tyrosine, 2 isomers of tyrosine that would not be present in normal proteins. In 3 different murine models of cancer that generate CR, both meta- and ortho-tyrosine inhibited tumor growth. Additionally, we showed that both isoforms of tyrosine blocked metastasis in a fourth model that does not generate CR but is sensitive to CR induced by other tumors. Mechanistic studies showed that the antitumor effects of the tyrosine isomers were mediated in part by early inhibition of the MAP/ERK pathway and inactivation of STAT3, potentially driving tumor cells into a state of dormancy in G(0)-phase. Other mechanisms, putatively involving the activation of an intra-S-phase checkpoint, would also inhibit tumor proliferation by accumulating cells in S-phase. By revealing a molecular basis for the classical phenomenon of CR, our findings may stimulate new generalized approaches to limit the development of metastases that arise after resection of primary tumors or after other stressors that may promote the escape of metastases from dormancy, an issue that is of pivotal importance to oncologists and their patients.

Caracterización del cáncer de mama en mujeres de la Argentina. Grupo Colaborativo para el Estudio del Cáncer de Mama en la Argentina. PROYCAM2012 / Characterization of breas cancer in woman of Argentina. Collaborative Group for the Study of Breast Cancer in Argentina. PROYCAM2012

En la Argentina el cáncer de mama con un 25 por ciento del total es la neoplasia maligna más común en las mujeres. El objetivo del presente trabajo es describir el perfil epidemiológico, clínico y patológico de mujeres con cáncer de mama concurrentes a centros asistenciales, públicos y privados del país, adheridos voluntariamente al Grupo Colaborativo durante el período 2012-2013. De los 607 casos reportados corresponden un 27 por ciento al sector público y un 73 por ciento al privado. Según subsectores: de obra social, 63.7 por ciento; sin cobertura, 19.7 por ciento; sistema prepago, 14.2 por ciento y mutal, 2.2 por ciento. Los casos por jurisdicciones fueron: Mendoza, 20.5 por ciento; CABA, 19.9 por ciento; Buenos Aires, 13.6 por ciento; Tucumán, 10.8 por ciento; Córdoba, 6.9 por ciento ; Río Negro, 4.9 por ciento y el resto del país, 23 por ciento. Edad de presentación promedio fue de 57.5 años, Con un rango de 63.4 (90.6-27.9). La mayor frecuencia se dio entre los 50-59 años con un 27.2 por ciento. Estadios: El pTNM de presentación en 506 casos fue: estadio 0: 5.9 por ciento; I: 37.7 por ciento; II: 35.7 por ciento; III: 18.8 por ciento y IV: 1.5 por ciento. Un estudio epidemiológico colaborativo sobre el cáncer de mama brinda información sobre las características biológicas y epidemiológicas en un breve lapso, considerando diferencias geográficas, socio-demográficas, biológicas e institucionales subyacentes en la prevención y el diagnóstico de esta patología. (AU)

In Argentina breast cancer with 25 percent of the total is the most common malignancy in women. The aim of this paper is to describe the epidemiological, clinical and pathologic women attending breast cancer care centers, public an private, voluntarily adhered to a Collaborative Group for the period 2012-2013. Of the 607 cases reported 27 percent are from the public and 73 percent from private sector. According to the subsectors they were from : social work, 63.7 percent; uninsured, 19.7 percent; prepaid system, 14.2 percent and mutual, 2.2 percent. Cases by jurisdictions were: Mendoza, 20.5 percent; CABA, 19.9 percent; Buenos Aires, 13.6 percent; Tucumán, 10.8 percent; Córdoba, 6.9 percent ; Río Negro, 4.9 percent and rest of the country, 23 percent. Average age at presentation was 57.5 years, with a range 63.4 years (90.6-27.9). The highest frequency was between 50-59 years with 27.2 percent. The pTNM of 506 cases was: stage 0: 5.9 percent; I: 37.7 percent; II: 35.7 percent; III: 18.8 percent and IV: 1.5 percent. A colaborative epidemiology study on breast cancer provides information on the biological and epidemiology in a short time, considering geographical, socio-demographic, biological and institutional differences underlying the prevention and diagnosis of this pathology. (AU)

Caracterización del cáncer de mama en mujeres de la Argentina. Grupo Colaborativo para el Estudio del Cáncer de Mama en la Argentina. PROYCAM2012 / Characterization of breas cancer in woman of Argentina. Collaborative Group for the Study of Breast Cancer in Argentina. PROYCAM2012

En la Argentina el cáncer de mama con un 25 por ciento del total es la neoplasia maligna más común en las mujeres. El objetivo del presente trabajo es describir el perfil epidemiológico, clínico y patológico de mujeres con cáncer de mama concurrentes a centros asistenciales, públicos y privados del país, adheridos voluntariamente al Grupo Colaborativo durante el período 2012-2013. De los 607 casos reportados corresponden un 27 por ciento al sector público y un 73 por ciento al privado. Según subsectores: de obra social, 63.7 por ciento; sin cobertura, 19.7 por ciento; sistema prepago, 14.2 por ciento y mutal, 2.2 por ciento. Los casos por jurisdicciones fueron: Mendoza, 20.5 por ciento; CABA, 19.9 por ciento; Buenos Aires, 13.6 por ciento; Tucumán, 10.8 por ciento; Córdoba, 6.9 por ciento ; Río Negro, 4.9 por ciento y el resto del país, 23 por ciento. Edad de presentación promedio fue de 57.5 años, Con un rango de 63.4 (90.6-27.9). La mayor frecuencia se dio entre los 50-59 años con un 27.2 por ciento. Estadios: El pTNM de presentación en 506 casos fue: estadio 0: 5.9 por ciento; I: 37.7 por ciento; II: 35.7 por ciento; III: 18.8 por ciento y IV: 1.5 por ciento. Un estudio epidemiológico colaborativo sobre el cáncer de mama brinda información sobre las características biológicas y epidemiológicas en un breve lapso, considerando diferencias geográficas, socio-demográficas, biológicas e institucionales subyacentes en la prevención y el diagnóstico de esta patología.

In Argentina breast cancer with 25 percent of the total is the most common malignancy in women. The aim of this paper is to describe the epidemiological, clinical and pathologic women attending breast cancer care centers, public an private, voluntarily adhered to a Collaborative Group for the period 2012-2013. Of the 607 cases reported 27 percent are from the public and 73 percent from private sector. According to the subsectors they were from : social work, 63.7 percent; uninsured, 19.7 percent; prepaid system, 14.2 percent and mutual, 2.2 percent. Cases by jurisdictions were: Mendoza, 20.5 percent; CABA, 19.9 percent; Buenos Aires, 13.6 percent; Tucumán, 10.8 percent; Córdoba, 6.9 percent ; Río Negro, 4.9 percent and rest of the country, 23 percent. Average age at presentation was 57.5 years, with a range 63.4 years (90.6-27.9). The highest frequency was between 50-59 years with 27.2 percent. The pTNM of 506 cases was: stage 0: 5.9 percent; I: 37.7 percent; II: 35.7 percent; III: 18.8 percent and IV: 1.5 percent. A colaborative epidemiology study on breast cancer provides information on the biological and epidemiology in a short time, considering geographical, socio-demographic, biological and institutional differences underlying the prevention and diagnosis of this pathology.

Tyrosine isomers mediate the classical phenomenon of concomitant tumor resistance.

Concomitant tumor resistance (CR) is a phenomenon originally described in 1906 in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. Although recent studies have indicated that T-cell-dependent processes mediate CR in hosts bearing immunogenic small tumors, manifestations of CR induced by immunogenic and nonimmunogenic large tumors have been associated with an elusive serum factor. In this study, we identify this serum factor as tyrosine in its meta and ortho isoforms. In three different murine models of cancer that generate CR, both meta-tyrosine and ortho-tyrosine inhibited tumor growth. In addition, we showed that both isoforms of tyrosine blocked metastasis in a fourth model that does not generate CR but is sensitive to CR induced by other tumors. Mechanistic studies showed that the antitumor effects of the tyrosine isoforms were mediated, in part, by early inhibition of mitogen-activated protein/extracellular signal-regulated kinase pathway and inactivation of STAT3, potentially driving tumor cells into a state of dormancy. By revealing a molecular basis for the classical phenomenon of CR, our findings may stimulate new generalized approaches to limit the development of metastases that arise after resection of primary tumors, an issue of pivotal importance to oncologists and their patients.

Biphasic effect of a primary tumor on the growth of secondary tumor implants.

BACKGROUND: The phenomenon of hormesis is characterized by a biphasic dose-response, exhibiting opposite effects in the low- and high-dose zones. In this study, we explored the possibility that the hormesis concept may describe the interactions between two tumors implanted in a single mouse, such that the resulting tumors are of different sizes. MATERIALS AND METHODS: We used two murine tumors of spontaneous origin and undetectable immunogenicity growing in BALB/c mice. A measure of cell proliferation was obtained by immunostaining for Ki-67 protein and by using the [(3)H] thymidine uptake assay. For serum fractionation, we utilized dialysis and chromatography on Sephadex G-15. RESULTS: The larger primary tumor induced inhibitory or stimulatory effects on the growth of the smaller secondary one, depending on the ratio between the mass of the larger tumor relative to that of the smaller one, with high ratios rendering inhibition and low ratios inducing stimulation of the secondary tumor. CONCLUSION: Since metastases can be considered as natural secondary tumor implants in a tumor-bearing host and that they constitute the main problem in cancer pathology, the use of the concept of hormesis to describe those biphasic effects might have significant clinical implications. In effect, if the tumor-bearing host were placed in the inhibitory window, tumor extirpation could enhance the growth of distant metastases and, reciprocally, if placed in the stimulatory window, tumor extirpation would result not only in a reduction or elimination of primary tumor load but also in a slower growth or inhibition of metastases.

Mouse mammary tumors display Stat3 activation dependent on leukemia inhibitory factor signaling.

INTRODUCTION: It has been demonstrated that leukemia inhibitory factor (LIF) induces epithelium apoptosis through Stat3 activation during mouse mammary gland involution. In contrast, it has been shown that this transcription factor is commonly activated in breast cancer cells, although what causes this effect remains unknown. Here we have tested the hypothesis that locally produced LIF can be responsible for Stat3 activation in mouse mammary tumors. METHODS: The studies were performed in different tumorigenic and non-tumorigenic mammary cells. The expression of LIF and LIF receptor was tested by RT-PCR analysis. In tumors, LIF and Stat3 proteins were analyzed by immunohistochemistry, whereas Stat3 and extracellular signal-regulated kinase (ERK)1/2 expression and phosphorylation were studied by Western blot analysis. A LIF-specific blocking antibody was used to determine whether this cytokine was responsible for Stat3 phosphorylation induced by conditioned medium. Specific pharmacological inhibitors (PD98059 and Stat3ip) that affect ERK1/2 and Stat3 activation were used to study their involvement in LIF-induced effects. To analyze cell survival, assays with crystal violet were performed. RESULTS: High levels of LIF expression and activated Stat3 were found in mammary tumors growing in vivo and in their primary cultures. We found a single mouse mammary tumor cell line, LM3, that showed low levels of activated Stat3. Incidentally, these cells also showed very little expression of LIF receptor. This suggested that autocrine/paracrine LIF would be responsible for Stat3 activation in mouse mammary tumors. This hypothesis was confirmed by the ability of conditioned medium of mammary tumor primary cultures to induce Stat3 phosphorylation, activity that was prevented by pretreatment with LIF-blocking antibody. Besides, we found that LIF increased tumor cell viability. Interestingly, blocking Stat3 activation enhanced this effect in mammary tumor cells. CONCLUSION: LIF is overexpressed in mouse mammary tumors, where it acts as the main Stat3 activator. Interestingly, the positive LIF effect on tumor cell viability is not dependent on Stat3 activation, which inhibits tumor cell survival as it does in normal mammary epithelium.

Selection of early-occurring mutations dictates hormone-independent progression in mouse mammary tumor lines.

Mice harboring three mouse mammary tumor virus (MMTV) variants develop pregnancy-dependent (PD) tumors that progress to pregnancy-independent (PI) behavior through successive passages. Herein, we identified 10 predominant insertions in PI transplants from 8 independent tumor lines. These mutations were also detected in small cell populations in the early PD passages. In addition, we identified a new viral insertion upstream of the gene Rspo3, which is overexpressed in three of the eight independent tumor lines and codes for a protein very similar to the recently described protein encoded by Int7. This study suggests that during progression towards hormone independence, clonal expansion of cells with specific mutations might be more relevant than the occurrence of new MMTV insertions.