Decidua mesenchymal stem cells migrated toward mammary tumors in vitro and in vivo affecting tumor growth and tumor development.

Mesenchymal stem cells (MSCs) have affinity to tumor sites where they home, affecting their biology and growth. Previously, we have isolated mesenchymal cells from the decidua of the human placenta named as decidua-derived MSCs (DMSCs). The aims of the present study were to investigate the migration capacity of DMSCs in vitro, and in vivo in a preclinical model of mammary tumors induced by N-nitroso-N-methylurea (NMU). Additionally, we assessed the safety of DMSC administration in vivo and their effect on tumor growth. In vitro studies showed that DMSCs significantly migrate toward both, healthy human breast tissue and breast adenocarcinoma. Nevertheless, the effect on DMSC migration was significantly higher in the presence of tumor tissue. DMSCs also significantly migrated in vitro in the presence of NMU-mammary tumor homogenate when compared with control media alone. In vivo studies showed both migration and engraftment of DMSCs into NMU-induced tumors. Interestingly, DMSCs showed an inhibitory effect on the growth of primary tumors and in the development of new tumors. DMSCs did not affect the growth of secondary tumors, although secondary tumors appeared 2 weeks later, and the number of secondary tumors was lower in the DMSC-treated rats as compared with vehicle-treated rats. To our knowledge, this is the first report showing placental MSCs effect on tumor growth. In conclusion, DMSCs could serve as a therapeutic agent themselves and as a cellular vehicle of anticancer drugs.

Tumour VEGF/non tumour VEGF protein expression ratio as a biomarker for survival in colorectal cancer patients.

AIMS: Vascular endothelial growth factor (VEGF) over-expression is frequently considered as a marker of both, a poor prognosis and of an aggressive tumour phenotype. Colorectal carcinoma is still one of the most lethal malignancies. Thus, our purpose was to study the expression of VEGF in tumour tissue (VEGF(t)) and in the tissue surrounding tumours (VEGF(nt)) and analyse its correlation with clinico-pathological features and overall survival. METHODS: The study was designed to determine the concentration of vascular endothelial growth factor in tumour (n = 87) and non-tumour tissue (n = 230) obtained form the colorectal cancer patients. Accordingly, VEGF expression was studied in tissue homogenates by a quantitative sandwich ELISA method. RESULTS: The study was performed on 317 colorectal samples from 87 colorectal cancer patients. VEGF expression was higher in the tumour than in the non-tumour area (P < 0.0005). In areas of 5-10 cm around the tumours, VEGF expression was higher than the expression obtained in proximal or distal edge of the resection. VEGF(t) expression was lower in patients with stage I than in patients with stage II, III, or IV. However, a shorter overall survival time was evident when the ratio obtained between VEGF expression in the tumour and mean VEGF expression in the non-tumour areas of the same patient (VEGF(t)/VEGF(nt) ratio) was ≤2 (P = 0.019). CONCLUSIONS: VEGF expression in colorectal cancer tissue was higher in tumour than in non-tumour areas. VEGF(t) expression was lower in initial clinical stages. Indeed, patients who presented a VEGF(t)/VEGF(nt) ratio >2 survived longer. This is the first report showing that the clinical outcome could be related to the VEGF(nt) over-expression in colorectal cancer patients.

Modulation of hepatocyte growth factor plasma levels in relation to the dose of exogenous heparin administered: an experimental study in rats.

INTRODUCTION: Partial liver transplantation has been consolidated to be a valid treatment option. We sought to understand the factors that modulate and may be harnessed to accelerate hepatocyte regeneration. We sought to determine the impact of heparin on m-hepatocyte growth factor (HGF) plasma concentrations. MATERIALS AND METHODS: Sixteen rats were assigned to four groups of four animals each: group A, without heparin; group B, 600 IU/kg; group C, 1000 IU/kg, group D, 1400 IU/kg. Blood samples (0.5 mL) were obtained from each rat at baseline and at 30, 60, 120, and 240 minutes. After the samples were centrifuged to separate supernates from the cell phase they were stored at -20 degrees C in the m-HGF reagent and subsequently tested using enzyme-linked immunosorbent assay. Results were analyzed using SPSS 11.5 statistical software. RESULTS: Among the 16 rats, one died at 110 minutes, just prior to the last extraction. The remaining rats were sacrificed. Mean weight was: 466 +/- 64.24 g with no intergroup differences (P = .149). The comparative results (using Student t test) were: baseline A(1-4) versus A(1-4) 30 minutes: P < .05; baseline A(1-4) versus A(1-4) 60 minutes: P < .05; baseline A(1-4) versus A(1-4) 120 minutes: P = .10 (NS); baseline A(1-4) versus A(1-4) 240 minutes: P = .15 (NS). No significant differences were found among group B: baseline C(1-4) versus C(1-4) 30 minutes and 60 minutes: NS; baseline C(1-4) versus C(1-4) 120 minutes: P < .001; baseline C(1-4) versus C(1-4) 240 minutes: P < .10 (NS). Finally, the results in group D were: baseline D(1-4) versus D(1-4) 30 minutes: NS; baseline D(1-4) versus D(1-4) 60 minutes and 120 minutes: P < .05; baseline D(1-4) versus D(1-4) 240 minutes: P < .0005. When we compared group A to C and D, we detected differences (albeit not when compared to B) with P values = .01. Peak values were obtained at 120 and 240 minutes (225.21 pg/mL and 221.78 pg/mL) among groups C and D. CONCLUSION: Heparin has a positive effect to increase serum HGF concentrations among rats. The effect was dependent on the administered dose and the time elapsed.

Tissue CA-19.9 content in colorectal adenomas and its value in the assessment of dysplasia.

BACKGROUND: occasionally, the risk of malignant transformation may be difficult to establish in adenomatous polyps due to the fact that they contain areas with variable grades of dysplasia. A measurement of tissue tumor markers may be useful to recognize these adenomas. OBJECTIVES: the aims of this study were: to established firstly the relationship between carbohydrate antigen 19.9 (CA-19.9) content in the colorectal mucosa and the characteristics of polyps, and secondly, the diagnostic value of the formers measurement. PATIENTS AND METHODS: tissue CA-19.9 concentration was measured in 155 colorectal samples obtained from 145 patients (21 normal mucosa; 113 adenomatous polyps; 21 adenocarcinoma). Cytosol CA-19.9 content was determined by enzyme-linked immunoadsorbant assay, and the measurement of this protein was achieved by quantitative assay. Tissue samples were also processed for histological examination. RESULTS: we demonstrated that CA-19.9 levels in adenomatous polyps and adenocarcinomas were significantly higher than in the normal mucosa. These levels varied significantly according to polyp size, histological type, and grade of dysplasia. CA-19.9 contents were higher in polyps with a high risk of malignant transformation than in those with a low risk of severe dysplasia. The cut-off value 214 U/mg of protein properly differentiated both types of risk. The area under the receiver operating characteristic (ROC) curves showed that cytosol CA-19.9 levels allow classifying polyps according to their histological features. CONCLUSIONS: we concluded that the measurement of CA-19.9 content in adenomatous polyps may be useful to classify these tumors and confirm the feasibility to separate adenomas into two groups: low and high risk of malignant change.

Survival of patients with colorectal carcinoma: possible prognostic value of tissular carbohydrate antigen 19.9 determination.

BACKGROUND: An important goal of serum tumor marker research is to provide a test for detecting cancer in early stages. Expression of carbohydrate antigen (CA) 19.9 has been described in various malignancies. METHODS: The possible prognostic value measuring cytosol CA 19.9 expression in tumors was evaluated in a study of 63 colorectal carcinoma (CRC) patients who were followed for at least 2 years. CA 19.9 expression in cytosol was determined by enzyme-linked immunoadsorbant assay, and measurement of this protein achieved by quantitative assay. RESULTS: Mean levels of cytosol CA 19.9 found in tumor samples were significantly higher than those in nontumoral areas in CRC patients (P<0.0005). Patients with more than 3 positive lymph nodes had a higher expression of the marker (P<0.05). Univariate and multivariate analyses revealed that cytosol CA 19.9 concentration was an independent prognostic variable for relapse. Furthermore, the probability of relapse increased 4.2 times for every increase in cytosol tumor marker of 5000 U/mg, and tumors located in the rectum had a probability of relapse 9.5 times greater. CONCLUSIONS: Cystol CA 19.9 expression in CRC can be an independent prognostic factor for relapse. Patients with high levels of CA 19.9 have worse prognosis than those with lower values. Therefore, this group of patients should receive special management with regard to their follow-up and treatment. Moreover, quantitative cytosol tumor marker measurement is an easy and highly effective method for determining the prognoses of CRC patients.

Prolactin response to dopamine and valproate administration in breast cancer patients.

There is only indirect evidence available at present to suggest the role of prolactin (PRL) in either the promotion or progression of human breast cancer. In order to determine if dopaminergic and GABAergic regulation of PRL are similar in breast cancer patients, we studied 2 groups of premenopausal women with no evident endocrine alteration: 1) control subjects (C); and 2) breast cancer patients (CA). Basal PRL levels were measured and their response to dopamine (DA) infusion (0.004 micrograms/kg/min) and valproate administration (400 mg/p.o.). The mean of percentage inhibition by DA in C (n = 6) was significantly higher than in CA (n = 11) at 180 min; P less than 0.025. On the other hand, group C (n = 8) responded to valproate with maximal inhibition at 180 min; in the CA group (n = 8) no inhibition was observed; P less than 0.0025.

Ornithine decarboxylase activity, prolactin blood levels, and estradiol and progesterone receptors in human breast cancer.

Ornithine decarboxylase (ODC) activity in human breast cancer tissues was correlated with prolactinemia (Prl), estradiol and progesterone cytosol receptors (ER and PR), and histopathologic pattern. Ninety-two cases of breast cancer, six benign mammary disease, and three normal breast tissues were studied for ER, PR, and ODC. Prolactinemia was assessed in 59 cancer patients, 14 of whom showed hyper-Prl along with significantly higher ODC than in patients with normal-Prl [(20.01 +/- 6.33) 10(-2) vs (5.20 +/- 0.90) 10(-2) pmol CO2/micrograms protein/h; P less than 0.0125]. A direct correlation was found between Prl and ODC in postmenopausal women (n = 40). Prl was assayed in seven of 13 ER-PR breast cancer patients; a highly significant, direct correlation was found between Prl and ODC in this group (r = 0.934, P less than 0.0025). ODC did not correlate with ER or PR. Carcinomas with higher ODC (n = 17) had higher cellularity, lower histologic differentiation, and higher nuclear anaplasia than those in which ODC was not detectable (n = 13). In normal breast and five of six benign mammary disease tissues, ODC was not detectable. These findings suggest that ODC could be a reliable marker for prognosis.

In vivo blockade of the estradiol-binding-protein (EBP) by clomiphene citrate in human breast cancer.

PIP: The effect of clomiphene citrate given in vivo upon the in vitro uptake of labeled estradiol (tritiated-E2) was investigated in a 60-year-old patient with breast cancer who had had a mastectomy 10 months earlier followed by radiotherapy. Multiple subcutaneous metastatic nodules and enlargement of the liver were present but bone metastases could not be shown. A biopsy from a subcutaneous nodule, taken prior to present treatment, showed 86 fmol estradiol binding sites per mg of cytoplasmic protein with a dissociation constant of the estradiol-estradiol binding protein interaction of 2.8 X 10 -10 M. The patient was treated with 200 mg clomiphene citrate daily. Subjective symptoms improved and a reduction of skin nodule size and of liver enlargement followed. The serum enzymes alkaline phosphatase, nucleotidase, and phosphohexoseisomerase were diminished. A 2nd biopsy taken at Day 26 of treatment with clomiphene citrate showed complete inhibition of labeled estradiol tritiated-E2 uptake by the cytosol protein. This finding is thought to show the absence of free binding sites after clomiphene citrate therapy. Microscopic studies of biopsy material were unchanged. These results are thought to be the first to record human in vivo inhibition of trititated-E2 uptake for EBP by an antiestrogen compound, although similar in vitro observations have been made in human tumor specimens. There is thought to be a potential value of antiestrogenic agents, alone or with inhibitors of prolactin secretion, to replace endocrine ablations and to predict the response to endocrine therapy.^ieng