PDGFRß promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma.

BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRß. Blocking PDGFRß kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRß-driven human ALCL in vivo, we identify PDGFRß as a driver of aggressive tumor growth. Mechanistically, PDGFRß induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. CONCLUSIONS: We therefore propose PDGFRß as a novel biomarker and introduce PDGFRß-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRß or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.

Arrest of the growth plate after arterial cannulation in infancy.

Seven children who had partial arrest of the growth plate after neonatal arterial cannulation, developed obvious skeletal changes in adolescence. Cannulation of the femoral artery produced ischaemia which led to four cases of ipsilateral shortening of the lower limb and one of partial arrest of the proximal femoral physis with subsequent coxa valga. The two arrests in the upper limb affected the humerus, ulna and radius, and the radius alone, after cannulation of the brachial and radial arteries, respectively. These late effects of cannulation are not widely appreciated, and may occur as a result of thrombosis rather than extravasation.

Molecular dissection of regulated secretory pathways in human gastric enterochromaffin-like cells: an immunohistochemical analysis.

Enterochromaffin-like (ECL) cells regulate gastric acid secretion through vesicular release of histamine. Until now, the molecular machinery of human ECL cells involved in the formation and release of vesicles is largely unknown. We analyzed tissue samples obtained from normal human gastric mucosa (n=4) and ECLomas (n=5) immunohistochemically using the APAAP method or double immunofluorescence confocal laser microscopy. Human pheochromocytomas (n=5) were investigated in parallel and compared to ECL cells. Secretory pathways were characterized using antibodies specific for marker proteins of large dense-core vesicles (LDCVs; islet cell antigen 512, chromogranin A, pancreastatin, and vesicular monoamine transporter 2) and small synaptic vesicle (SSV) analogues (synaptophysin). Tissues were also analyzed for expression of the peptide hormone processing enzymes, carboxypeptidase E and prohormone convertase 1, as well as the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, 25-kDa synaptosome-associated protein (SNAP25), syntaxin, and synaptobrevin. Immunoreactivity for markers of LDCVs and SSV analogues were detected in normal ECL cells and ECLomas. Both tissues also showed expression of carboxypeptidase E and prohormone convertase 1. Analysis of vesicular SNARE (v-SNARE) and target membrane SNARE (t-SNARE) proteins revealed the presence of SNAP25, syntaxin, and synaptobrevin in normal and neoplastic ECL cells. Our data suggest that ECL cells possess the two vesicle types of regulated neuroendocrine secretory pathways, LDCVs and SSV analogues. Since ECL cells also contain typical SNARE proteins, the molecular machinery underlying secretory processes in this cell type appears to be identical to the secretory apparatus of neuroendocrine cells and neurons. In addition, our findings suggest that the secretory apparatus of ECL cells is maintained during neoplastic transformation.

ALK gene products in anaplastic large cell lymphomas and Hodgkin's disease.

The translocation t(2;5)(p23;q35), discovered in CD30+ anaplastic large cell (ALC) lymphomas, creates a potentially oncogenic fusion gene, part of which is contributed by a novel tyrosine kinase, ALK. Absence of ALK expression from normal hematolymphoid cells provides a basis for the morphologic assessment of t(2;5). The distribution of the t(2;5) in ALC lymphomas and Hodgkin's disease (HD), as assayed by nonmorphologic methods, is controversial. We used in situ hybridization and/or immunohistology to show ALK gene products in 85 ALC lymphomas, 82 HD cases, 40 other lymphoproliferations, as well as in 6 HD- and 4 ALC lymphoma-derived cell lines. ALK gene products were restricted to t(2;5)-positive ALC lymphoma cell lines and tumor cells of 16 primary non-B cell, common-type ALC lymphomas. These were mainly from young patients with initial lymphonodal disease. ALK expression was not detectable in any other specimen, including all cases of HD and HD-like type ALC lymphoma as well as secondary ALC lymphomas. Full congruence was noted for labeling results obtained with both methods. In agreement with cytogenetic analyses, but at variance with recently published studies, ALK gene expression distinguishes a subset of ALC lymphomas from other CD30+ lymphomas, including HD. The results do not support concepts attributing a significant role to the t(2;5) in the development of HD.

Epstein-Barr virus and gastric cancer: data and unanswered questions.

Sixty-five unselected cases of gastric cancer have been analysed for EBV DNA by polymerase chain reaction, in situ hybridization and immunohistochemistry for CD21 antigen expression. Four cases were found EBV-positive by PCR, while ISH yielded positive results in 3 of these cases, demonstrating EBV in the nuclei of cancerous cells. CD21 antigen was expressed in cancerous cells in all 3 ISH-positive cases. All the EBV-positive cancers of the present series were poorly to moderately differentiated adenocarcinomas with prominent lymphoid infiltration. These results are discussed also on the basis of the literature.

Solitary intracranial extracerebral glioma.

The authors present the case of a 65-year-old woman with a solitary extracerebral glioma. The tumour originated from the falx in the left fronto-parietal region near the paracentral lobule. Because it was well delineated and was completely outside the brain it was thought at operation to be a meningioma or a metastasis. Histologically the tumour could be classified as an oligodendroglioma (WHO grade II). Intracranial extracerebral gliomas so far described are most frequently located in the vicinity of the sylvian fissure. Involvement of the dura has only been observed in three cases. This case is to the best of our knowledge the only one in which the tumour was situated in the longitudinal fissure having originated from the falx. Extracerebral gliomas are thought to arise from heterotropic nests of glial cells in the leptomeninges.

Morphologic evaluation of stereotactic brain tumour biopsies.

The validity of morphologic diagnosis of stereotactic brain tumour biopsies was evaluated in a series of 600 patients treated since 1977 at the University Hospital, Freiburg. Combined cytological (smear preparations) and histological examination of paraffin-embedded samples revealed the tumour type and approximate grading in 492 (82%) of cases. In 66 patients a clinically suspected neoplasm could be ruled out. In the remaining 42 cases (7%), the presence of a tumour was confirmed but the available samples did not allow an unequivocal classification of the neoplasm. Inaccurate diagnoses were most frequently due to sampling errors in non-homogeneous tumours, i.e. biopsies taken from sites not representative for the entire neoplasm (tumour necroses, infiltration zone). In the future, the use of immunohistochemical methods for the identification of tumour markers and cytoskeleton proteins may partially compensate for the limited size of stereotactic biopsy samples.