Paget's disease of the nipple without clinically and radiologically detectable breast tumor. Histochemical and immunohistochemical study of 44 cases.

Paget's disease of the nipple is a rare lesion nearly always associated with an underlying breast cancer, clinically impalpable and radiologically undetectable in about 40% of the patients. Fourty-four cases (28 mastectomies and 16 biopsies of the nipple) of Paget's disease of the nipple without clinically and radiologically detectable breast tumor were retrospectively studied by means of histochemistry and immunohistochemistry. Histochemical study showed that Paget cells were PAS positive and diastase resistant, and alcian blue positive at pH 2.5 in 32% and 18%, respectively. Immunohistochemical study showed that Paget cells were EMA and c-erbB-2 positive in 100% and 84%, respectively. Four of the six EMA positive and c-erbB-2 negative cases of Paget's disease of the nipple in which the underlying tumor could be pathologically analyzed were associated with ductal carcinoma in situ of cribriform or mixed types. These findings are helpful for differentiating Paget's disease from other lesions of the nipple, namely Bowen's disease and eczema which do not react with both antibodies, and from nipple adenoma which exhibits a positive staining with anti-EMA antibody and no reactivity with anti-c-erbB-2 antibody.

[CSF-1 (colony stimulating factors 1) and CSF-1 receptor. General review and expression in invasive breast tumors]. / CSF-1 (colony stimulating factor 1) et récepteur du CSF-1. Revue générale et expression dans les tumeurs mammaires invasives.

CSF-1 (colony stimulating factor-1), initially considered to be a monocyte specific growth and differentiation factor [4], has recently been shown to be produced in human endometrium [16], placenta [7], as well as in numerous solid tumors [19-23, 26, 27]. The CSF-1 receptor (a protein product of c-fms) [24] is a member of the tyrosine kinase receptor family and an autocrine or paracrine mechanism of activation has been suggested. Overactivation of this receptor can lead to a malignant phenotype in various cell systems [20, 21]. We review the biology of CSF-1 and fms expression in normal as well as in malignant tissues with particular reference to a potential role for CSF-1 in breast tumour invasion.

The serine-threonine kinase p90RSK is a new target of enzastaurin in follicular lymphoma cells.

BACKGROUND AND PURPOSE: Follicular lymphoma is the second most common non-Hodgkin's lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl-2, Bcl-6 or c-Myc, follicular lymphoma cells often display altered B-cell receptor signalling pathways including overactive PKC and PI3K/Akt systems. EXPERIMENTAL APPROACH: The effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment. KEY RESULTS: Enzastaurin inhibited the serine-threonine kinase p90RSK which has downstream effects on GSK3ß. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice. CONCLUSIONS AND IMPLICATIONS: The targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.

Involvement of the Syk-mTOR pathway in follicular lymphoma cell invasion and angiogenesis.

Follicular lymphoma (FL) is the second-most common non-Hodgkin's lymphoma. The disease affects the lymph nodes, and 50% of patients present with bone marrow infiltration; however, the mechanisms involved in dissemination of the disease are not yet known. We previously reported that FL cells display an overexpression of Syk, a tyrosine kinase involved in many cellular processes including cell migration. Therefore, we sought to explore its role in the invasive process. Here, we show that FL patients display higher matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF) levels than healthy donors. Moreover, using Syk small interfering RNA and the Syk inhibitor R406, we demonstrate that, in FL cells, Syk is involved in the regulation of MMP-9 and VEGF expression, and that invasion and angiogenesis is mediated through a phosphatidylinositol-3 kinase (PI3K)-mammalian target of rapamycin module. Finally, using a FL xenograft mouse model we observe that fostamatinib (R788), inhibits MMP-9 expression and angiogenesis in vivo. Altogether, this study provides strong evidence that Syk represents an encouraging therapeutic target in FL and suggests the potential use of fostamatinib as an anti-invasive and anti-angiogenic drug.

B-chronic lymphocytic leukemia chemoresistance involves innate and acquired leukemic side population cells.

B-cell chronic lymphocytic leukemia (B-CLL) therapy remains unsatisfactory due to repeated resurgences of the chemoresistant disease. In this study, we investigated the basis of this chemoresistance by applying the 'side population' (SP) analysis to blood samples from B-CLL patients. We report the existence of few natural SP cells, which harbors phenotypic and cytogenetic hallmarks of B-CLL in most patients with this disease (n=22). SP cells appeared resistant to conventional B-CLL treatments, such as Fludarabine, Bendamustin or Rituximab. Indeed, treatment with Fludarabine (16/18 cases) or Bendamustin (5/7 cases) resulted in complete elimination of non-SP, whereas cells displaying the SP phenotype were the only surviving. Although some B-CLL SP cells were innately chemoresistant, chemotherapy by Fludarabine selected not only innate SP cells but also induced some acquired SP cells, which arose from non-SP by drug-driven evolution. This SP selection by chemotherapeutic treatments is further supported by the overall increase of the SP percentage in patients who experienced chemotherapy in the preceding year. Functionally, proliferative stimulation of SP cells was able to partially replenish in vitro the non-SP cell compartment of the B-CLL disease. The chemoresistance of B-CLL relies, in our model, on the cellular heterogeneity of B-CLL SP cells and on their regenerating dynamics.