The International Society of Urological Pathology 2012 Consensus Conference made recommendations regarding classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. Issues relating to prognostic factors were coordinated by a workgroup who identified tumor morphotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and microvascular invasion as potential prognostic parameters. There was consensus that the main morphotypes of renal cell carcinoma (RCC) were of prognostic significance, that subtyping of papillary RCC (types 1 and 2) provided additional prognostic information, and that clear cell tubulopapillary RCC was associated with a more favorable outcome. For tumors showing sarcomatoid or rhabdoid differentiation, there was consensus that a minimum proportion of tumor was not required for diagnostic purposes. It was also agreed upon that the underlying subtype of carcinoma should be reported. For sarcomatoid carcinoma, it was further agreed upon that if the underlying carcinoma subtype was absent the tumor should be classified as a grade 4 unclassified carcinoma with a sarcomatoid component. Tumor necrosis was considered to have prognostic significance, with assessment based on macroscopic and microscopic examination of the tumor. It was recommended that for clear cell RCC the amount of necrosis should be quantified. There was consensus that nucleolar prominence defined grades 1 to 3 of clear cell and papillary RCCs, whereas extreme nuclear pleomorphism or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed upon that chromophobe RCC should not be graded. There was consensus that microvascular invasion should not be included as a staging criterion for RCC.

The gastrointestinal tract is constantly challenged by foreign antigens and commensal bacteria but nonetheless is able to maintain a state of immunological quiescence. Recent advances have highlighted the importance of active suppression by regulatory lymphocytes and immunosuppressive cytokines in controlling mucosal immunity. Failures of these mechanisms contribute to the development of inflammatory bowel disease, but how these regulatory networks are established remains unclear. Here, we demonstrate key roles for ␣v integrins in regulation of mucosal immunity. We report that deletion of ␣v in the immune system causes severe colitis, autoimmunity, and cancer. Mice lacking immune cell ␣v have fewer regulatory T (Treg) cells in the colon and corresponding increases in activated T cells and T cell cytokine production, leading to colitis. Using conditional gene targeting, we demonstrate that this is specifically attributable to loss of ␣v from myeloid cells. Furthermore, we show that gut-associated macrophages and dendritic cells fail both to remove apoptotic cells efficiently and to induce Treg cells. Our results identify a vital role for myeloid ␣v integrins in generating mucosal Treg cells and emphasize the importance of antigen-presenting cells in establishing immune tolerance.immunoregulation ͉ phagocytosis ͉ apoptotic ͉ dendritic cell ͉ regulatory T cell I ntegrins are dimeric cell-surface receptors composed of ␣ and ␤ subunits (1). ␣v is the most promiscuous ␣ subunit, associating with five different ␤ subunits (␤1, ␤3, ␤5, ␤6, and ␤8) and participates in many important cellular processes, including cell adhesion, migration, survival, and growth factor signaling. ␣v integrins are expressed in many tissues throughout development, and ␣v knockout mice die at midgestation from placental deficiencies or, immediately after birth, with cerebral and intestinal hemorrhage and cleft palate (2). The lethality of ␣v Ϫ/Ϫ mice is attributable mainly to loss of ␣v␤8, because ␤8 Ϫ/Ϫ mice show similar placental and neural vasculature abnormalities (3), and these defects are principally attributable to loss of ␣v␤8 from parenchymal tissues supporting blood vessels (4, 5). Knockouts of most other ␣v-associated ␤ integrins (␤3, ␤5, and ␤6) are viable and reveal roles for ␣v in repair of tissue injury, inflammation, and immune responses (1, 6-8). ␣v␤6 and ␣v␤8 are expressed in epithelium, where their functions include binding and activating TGF-␤ (9), and ␣v␤8 is also expressed by myeloid cells and T cells (10, 11). ␣v␤3 and ␣v␤5 are more widely expressed and are up-regulated by many cells after tissue injury. In the immune system, ␣v␤3 and ␣v␤5 are expressed by many different cell types and promote cell adhesion, migration, and survival. ␣v integrins also mediate the uptake of apoptotic cells (12-14), a process central to immune regulation and inflammation resolution (15).Here, we report that ␣v integrins are central to the normal regulation of immune responses in the intestine and that deletion of ␣v in the immune system lead...

Dissemination to draining lymph nodes is a frequent first step in prostate cancer metastasis. Although tumors metastasize to lymph nodes via the lymphatics, the importance of lymphangiogenesis in mediating the process remains controversial. Here, we inhibit intratumoral lymphangiogenesis in s.c. and surgical orthotopic implantation mouse models of human prostate cancer using several strategies. Stable expression of small interfering RNAs (siRNA) targeted against human vascular endothelial growth factor-C (VEGF-C) in PC-3 cells reduced intratumoral lymphatics by 99% in s.c. tumors, indicating that tumor-secreted VEGF-C is necessary for lymphangiogenesis. Expression of siRNAs against human VEGF-A somewhat reduced tumor lymphangiogenesis. Secretion of a soluble VEGF receptor-3/Flt4 fusion protein by PC-3 cells reduced intratumoral lymphatics by 100% in s.c. tumors. Combination of soluble Flt4 and VEGF-C siRNA yielded >92% reduction of intratumoral lymphatics in orthotopic prostate tumors. However, metastasis to lymph nodes was not significantly affected regardless of intratumoral lymphatic vessel density. The abundance of marginal lymphatics at the tumor-stromal interface was unchanged in orthotopic tumors whose intratumoral lymphatics were inhibited, suggesting that these marginal vessels could be sufficient for lymph node metastasis. Hematogenous metastasis (blood tumor burden, lung metastasis) correlated with degree of lymph node invasion. We also analyzed the lymphatics in spontaneous transgenic adenocarcinomas of the mouse prostate which metastasize to lymph nodes. Progression from well-differentiated prostate intraepithelial neoplasia to metastatic, undifferentiated adenocarcinoma was accompanied by loss of lymphatics. These results suggest that tumor-secreted VEGF-C and, to a lesser extent, VEGF-A, are important for inducing prostate cancer intratumoral lymphangiogenesis but are unnecessary for lymph node metastasis. (Cancer Res 2005; 65(21): 9789-98)

SUMMARY Transgenic expression of activated AKT1 in the murine prostate induces Prostatic Intraepithelial Neoplasia (PIN) that does not progress to invasive prostate cancer (CaP). In luminal epithelial cells of Akt-driven PIN we show the concomitant induction of p27kip1 and senescence. Genetic ablation of p27Kip1 led to down regulation of senescence markers and progression to cancer. In humans, p27Kip1 and senescence markers were elevated in PIN not associated with CaP, but were decreased and absent, respectively in cancer-associated PIN and in CaP. Importantly, p27Kip1 up-regulation in mouse and human in situ lesions did not depend upon mTOR or Akt activation but was instead specifically associated with alterations in cellular polarity, architecture and adhesion molecules. These data suggest that a p27Kip1-driven checkpoint limits progression of PIN to CaP.