Tunneling nanotubes are long, non-adherent F-actin-based cytoplasmic extensions which connect proximal or distant cells and facilitate intercellular transfer. The identification of nanotubes has been limited to cell lines, and their role in cancer remains unclear. We detected tunneling nanotubes in mesothelioma cell lines and primary human mesothelioma cells. Using a low serum, hyperglycemic, acidic growth medium, we stimulated nanotube formation and bidirectional transfer of vesicles, proteins, and mitochondria between cells. Notably, nanotubes developed between malignant cells or between normal mesothelial cells, but not between malignant and normal cells. Immunofluorescent staining revealed their actin-based assembly and structure. Metformin and an mTor inhibitor, Everolimus, effectively suppressed nanotube formation. Confocal microscopy with 3-dimensional reconstructions of sectioned surgical specimens demonstrated for the first time the presence of nanotubes in human mesothelioma and lung adenocarcinoma tumor specimens. We provide the first evidence of tunneling nanotubes in human primary tumors and cancer cells and propose that these structures play an important role in cancer cell pathogenesis and invasion.

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Purpose Recent evidence suggests that at least some sarcomas arise through aberrant differentiation of mesenchymal stromal cells (MSCs), but MSCs have never been isolated directly from human sarcoma specimens. Experimental Design We examined human sarcoma cell lines and primary adherent cultures derived from human sarcoma surgical samples for features of MSCs. We further characterized primary cultures as either benign or malignant by the presence of tumor-defining genetic lesions and tumor formation in immunocompromised mice. Results We show that a dedifferentiated liposarcoma cell line DDLS8817 demonstrates fat, bone and cartilage trilineage differentiation potential characteristic of MSCs. Primary sarcoma cultures have the morphology, surface immunophenotype and differentiation potential characteristic of MSCs. Surprisingly, many of these cultures are benign as they do not form tumors in mice and lack sarcoma-defining genetic lesions. Consistent with the recently proposed pericyte origin of MSCs in normal human tissues, sarcoma-derived benign MSCs express markers of pericytes and cooperate with endothelial cells in tube formation assays. In human sarcoma specimens, a subset of CD146-positive microvascular pericytes express CD105, an MSC marker, while malignant cells largely do not. In an in vitro co-culture model, sarcoma-derived benign MSCs as well as normal human pericytes markedly stimulate the growth of sarcoma cell lines. Conclusions Sarcoma-derived benign MSCs/pericytes represent a previously undescribed stromal cell type in sarcoma which may contribute to tumor formation.

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Матриксные металлопротеиназы (ММП)-семейство цинксодержащих эндопептидаз, катализирующих реакции деградации компонентов внеклеточного матрикса. У человека известно 23 фермента этого семейства, которые подразделяют на 6 групп с учетом их структуры и типа субстрата: коллагеназы, желатиназы, стромелизины, матрилизины, ММП мембранного типа и остальные ММП. Функции ММП разнообразны, и нарушение баланса их активности может быть одним из этиологических факторов различных заболеваний. В обзоре рассмотрены классификация, регуляция активности и генетический полиморфизм ММП в норме и при различных патологических процессах в организме человека. Приведен перечень наиболее изученных в настоящее время полиморфных вариантов генов MMП, описаны их функциональные эффекты и представлены результаты ассоциативных исследований.

5012 Background: VEGF receptor-mediated-signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression and serum levels are associated with poor clinical outcomes. We investigated RAM, a fully human VEGFR-2 antagonist antibody, in patients (pts) with persistent or recurrent EOC/FTC/PPC. Methods: Adult women with EOC/FTC/PPC who had completed ≥1 platinum (P)-based chemotherapeutic (ct) regimen and had a P-free interval (PFI) of <12 months (m), progression on, or persistent disease after P-based therapy were eligible. Any number of prior ct regimens was allowed. ECOG PS 0-1 and adequate organ function were required. Pts received 8 mg/kg RAM IV every 2 weeks. Primary endpoints were progression-free survival at 6m (PFS-6) and confirmed objective response rate (ORR) by RECIST 1.0. Results: 60 pts were treated; 1 remains on study as of Dec 2011. Median age was 62 years (range 27-80). Median number of prior regimens was 3 (range 1– 14). 51 pts (85%) received ≥ 2 prior regimens; 25 pts (42%) received >3 prior regimens. 45 pts (75%) were P resistant or refractory, with 65% (39 pts) serous tumors. PFS-6: 34.2% (95% CI: 21.7% – 47%). Best overall response: 3 PR (5%), 34 SD (57%), 20 PD (33%) and 3 not evaluable (5%). Median duration of PR: 5.6m (3.7, 5.6, 17.5); median PFS: 3.5m (95% CI: 2.3 – 5.3). Median OS: 11.1m (95% CI: 8.3 – 17.0). No unexpected toxicities were observed. Grade (G) 3 adverse events (AEs) observed in >5% of pts were: headache (10%) and fatigue (8%). No G4 AEs were observed in >5% of pts. 5 deaths occurred on RAM or within 30 days of discontinuation; 4 due to PD, and 1 due to intestinal perforation. 1 G4 bowel perforation and one G4 colo-vaginal fistula were noted. All 3 cases of perforation/fistula occurred in the setting of progressive, large-volume disease. Correlative biomarker studies are ongoing to identify patients most likely to benefit. Conclusions: Ramucirumab was reasonably tolerated and demonstrated single-agent activity in persistent or recurrent ovarian carcinoma, with approximately one-third of patients progression free at 6 months.

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Владимирович-врач-уролог, соискатель лаборатории клинической биохимии 1 Короткова Екатерина Андреевнаканд. биол. наук, ст. науч. сотр., лаборатория клинической биохимии 1 Бежанова Светлана Дмитриевнааспирант отдела патологической анатомии опухолей человека 1 Морозов Алексей Андреевич-врачуролог, отделение урологии 2 Алферов Александр Андреевичаспирант лаборатории клинической биохимии 1 Казанцева Ирина Александровнад-р мед. наук, профессор, вед. науч. сотр., патологоанатомическое отделение 2 Кушлинский Николай Евгеньевичд-р мед. наук, профессор, членкорреспондент РАН, заведующий лабораторией клинической биохимии 1