(9R)-9-chloro-11-17-dihydroxy-17-(2-hydroxy-1-oxoethyl)-10-13-16-trimethyl-6-7-8-11-12-14-15-16-octahydrocyclopenta[a]phenanthren-3-one and Breast-Neoplasms

Inhibition of VEGF signalling effectively suppresses localized tumour growth but accelerates tumour invasiveness and micrometastasis by unknown mechanisms. To study the dynamic and reciprocal interactions between tumour cells and their microenvironment during these processes, we established a xenograft model by injecting tumour cells into the blood circulation of transparent zebrafish embryos. This reproducibly results in rapid simultaneous formation of a localized tumour and experimental micrometastasis, allowing time-resolved imaging of both processes at single-cell resolution within 1 week. The tumour vasculature was initiated de novo by remodelling of primitive endothelial cells into a functional network. Roles of myeloid cells in critical tumourigenesis steps such as vascularization and invasion were revealed by genetic and pharmaceutical approaches. We discovered that the physiological migration of neutrophils controlled tumour invasion by conditioning the collagen matrix and forming the metastatic niche, as detected by two-photon confocal microscopy and second harmonic generation. Administration of VEGFR inhibitors blocked tumour vascularization and a localized tumour growth but enhanced migration of neutrophils, which in turn promoted tumour invasion and formation of micrometastasis. This demonstrates the in vivo cooperation between VEGF signalling and myeloid cells in metastasis and provides a new mechanism underlying the recent findings that VEGFR targeting can promote tumour invasiveness.

Topics: Animals; Beclomethasone; Breast Neoplasms; Cell Movement; Cell Transformation, Neoplastic; Disease Models, Animal; Endothelial Cells; Humans; Indoles; Mice; Myeloid Cells; Neoplasm Metastasis; Neutrophils; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sunitinib; Xenograft Model Antitumor Assays; Zebrafish

Efflux transporters, p-glycoprotein and breast cancer resistance protein (BCRP), located at barrier sites such as the blood-brain barrier may affect distribution of steroids used for treating chronic inflammatory conditions and thus the extent to which they may perturb the hypothalamic-pituitary-adrenal axis. In the present study, six different glucocorticoids were investigated for their possible interactions with these efflux transporters. Beclomethasone dipropionate, mometasone furoate and ciclesonide active principle but not fluticasone propionate or triamcinolone, (all at 0.1 to 10 microM) caused inhibition of efflux, resulting in increased accumulation of mitoxantrone in BCRP-expressing MCF7/MR breast cancer cells and of calcein in p-glycoprotein-expressing SW620/R colon carcinoma cell. At 5 microM the same three increased sensitivity of p-glycoprotein-expressing SW620/R to doxorubicin and stimulated ATPase activity associated with BCRP expressed in bacterial membrane vesicles. Budesonide also stimulated ATPase activity. These data demonstrate the capacity of some clinically used glucocorticoids to interact with efflux transporters.

Topics: Adenosine Triphosphatases; Adrenal Cortex Hormones; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Beclomethasone; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Fluoresceins; Humans; Mitoxantrone; Mometasone Furoate; Neoplasm Proteins; Pregnadienediols; Pregnenediones

The indication and extent of axillary lymph node dissection in breast cancer remains open to controversy.. In this context, a 20-year survival study has been made of 1600 breast cancer patients subjected during surgical treatment to systematic dissection of the acromiothoracic vascular pedicle together with the accompanying lymph nodes (Rotter and Grossman interpectoral lymph node groups). An anatomical study of these nodes was also conducted in 100 necropsies, with the evaluation of 200 acromiothoracic vascular pedicles.. The interpectoral lymph nodes were anatomically present in 42% of the necropsies and in 35.1% of the patients subjected to surgery. The prognosis was much worse in cases of neoplastic infiltration of the interpectoral lymph nodes (Kaplan-Meier survival study), regardless of the influence of other prognostic factors.. In view of the results obtained, the designation of grade N3 of the TNM classification is proposed for malignancies with positive interpectoral lymph node infiltration.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autopsy; Beclomethasone; Breast Neoplasms; Child; Child, Preschool; Dissection; Female; Genetic Variation; Humans; Infant; Life Tables; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Organ Specificity; Prognosis; Retrospective Studies; Survival Analysis; Thorax