Summary Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and PDGFRA amplification. Here, we describe a somatic mouse model wherein H3.3K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3K27M-driven lesions are clonal, H3K27me3-depleted, Olig2-positive, highly proliferative and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown associates with more circumscribed tumors. H3.3K27M-tumor cells serially engraft in recipient mice and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3K27M-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies.
Current treatment for metastatic disease targets angiogenesis. With the increasing data demonstrating that cancer cells do not entirely rely on angiogenesis but hijack the existing vasculature through mechanisms such as co‐option of existing blood vessels, identification of targets has become of utmost importance. Our study looks at the vasculature of chemonaïve and treated colorectal carcinoma liver metastases (CRCLMs) to obtain a basic understanding of the microvessel density, type of vasculature (mature versus immature), and correlation with histopathological growth patterns that demonstrate unique patterns of angiogenesis. We performed immunohistochemistry on chemonaïve sections of desmoplastic histopathological growth pattern (DHGP) and replacement histopathological growth patterns (RHGP) lesions with CD31 [endothelial cell (EC) marker] and CD34/Ki67 double staining, which denotes proliferating ECs. The CD31 stains demonstrated a lower microvascular CD31 +ve capillary density in the DHGP versus RHGP lesions; and integrating both immunostains with CD34/Ki67 staining on serial sections revealed proliferating vessels in DHGP lesions and co‐option of mature existing blood vessels in RHGP lesions. Interestingly, upon treatment with chemotherapy and bevacizumab, the RHGP lesions showed no necrosis whereas the DHGP lesions had almost 100% necrosis of the cancer cells and in most cases there was a single layer of viable cancer cells, just under or within the desmoplastic ring. The survival of these cells may be directly related to spatial location and possibly a different microenvironment, which may involve adhesion to different extracellular matrix components and/or different oxygen/nutrient availability. This remains to be elucidated. We provide evidence that DHGP CRCLMs obtain their blood supply via sprouting angiogenesis whereas RHGP lesions obtain their blood supply via co‐option of existing vasculature. Furthermore current treatment regimens do not affect RHGP lesions and although they kill the majority of the cancer cells in DHGP lesions, there are cells surviving within or adjacent to the desmoplastic ring which could potentially give rise to a growing lesion.
Colorectal cancer liver metastases (CRCLM) that receive their blood supply via vessel co-option are associated with a poor response to anti-angiogenic therapy. Angiopoietins (Ang1 and Ang2) with their Tyrosine-protein kinase receptor (Tie2) have been shown to support vessel co-option. We demonstrate significantly higher expression of Ang1 in hepatocytes adjacent to the tumor region of human chemonaïve and treated co-opting (replacement histopathological growth patterns: RHGP) tumors. To investigate the role of the host Ang1 expression, Ang1 knockout (KO) mice were injected intra-splenically with metastatic MC-38 colon cancer cells that develop co-opting liver metastases. We observed a reduction in the number of liver metastases and interestingly, for the first time, the development of angiogenic driven desmoplastic (DHGP) liver metastases. In addition, in-vitro, knockout of Ang1 in primary hepatocytes inhibited viability, migration and invasion ability of MC-38 cells. We also demonstrate that Ang 1 alone promotes the migration and growth of both human and mouse colon cancer cell lines These results provide evidence that high expression of Ang1 in the host liver is important to support vessel co-option (RHGP lesions) and when inhibited, favours the formation of angiogenic driven liver metastases (DHGP lesions).
Evaluations of education technology (ed tech) interventions in humanitarian settings are scarce. We present a proof-of-concept study of Can't Wait to Learn, a digital game-based learning program that combines an experiential, active learning design with meaningful, competency-appropriate, and contextually relevant content. We assessed the feasibility of using this program to address the current education gap in Lebanon by implementing its mathematics component in basic literacy and numeracy classes (n=30) with out-of-school children (n=390) ages 10-14. We estimated changes in numeracy competency and psychosocial wellbeing and conducted focus group discussions (n=16) and key informant interviews (n=19) with children, facilitators, parents, and partner staff members to understand the lived experience, perceived impact, and implementation challenges of the program. Our findings support the feasibility of using ed tech programs to meet the needs of out-of-school children, as we saw significant improvements in numeracy, psychological symptoms, and self-esteem; positive reported experiences with the program; increased motivation among the children; and overall ease of implementation. Our suggested improvements to the game design and implementation model will support ongoing program adaptation and implementation, with the goal of increasing access to quality education for children living in humanitarian settings. Our findings will inform future studies that seek to conclusively determine the program's effectiveness.
Colorectal cancer (CRC) is the third leading cause of cancer in Canadians, with liver metastases being the major cause of death from this disease. Tumors induce angiogenesis, a phenomenon known as the ‘angiogenic switch’, which is an essential step in tumor progression whereby the balance of pro- and anti-angiogenic factors are important for active angiogenesis. Clinical efficacy of targeted VEGF (anti-angiogenic) treatment has been validated as a cancer therapy. Our group, together with others, has identified unique histological growth patterns HGPs (desmoplastic, replacement and pushing) within liver metastases that have different responses to anti-angiogenic therapy. The patients with Desmoplastic HGP (DHGP) that received anti-angiogenic plus chemotherapy prior to resection had a significantly better pathologic response and survival than patients with Replacement HGP (RHGP). The aim of this study was to explore the role of Ang-1, Ang-2, Tie-2 and VEGF in the development and progression of CRCLM tumors with distinct HGPs. Here, human CRCLM tumor samples were analyzed by quantitative real-time PCR (Q-PCR) and immunohistochemistry (IHC) staining. The Q-PCR results demonstrated that the expression of Ang-2 was lower in RHGP tumor samples compared with DHGP tumor samples. This data was validated by IHC, were IHC scoring results showed that the ratio of Ang-2: Ang-1 expression in DHGP tumors was higher compared to RHGP tumors. VEGF and Tie2 proteins were expressed in both tumor patterns. Thus vascular quiescence maintained by constitutive Ang-1/Tie-2 signaling, found in RHGP tumors, prevails over destabilization and pro-inflammatory Ang-2/Tie-2 signaling, which is higher in the DHGP tumor samples. Since vascular remodelling is driven by Ang-2/Tie-2 in DHGP, which is dependent on VEGF we would expect anti-angiogenic therapy to be effective on DHGP. Furthermore, the RHGP had low levels of Ang-2 and high levels of Ang-1, together with the presence of Tie-2, and then one would predict that VEGF is not required for the growth of these tumors and thus would not respond to anti-angiogenic therapy, as has been shown in our patients’ cohort. Taken together, these data suggest that the Angiopoietin/Tie-2 functional axis is an important player in CRCLM tumor progression and can be a potential target for CRCLM cancer therapy with stratification of patients by HGPs. Citation Format: Nisreen S. Ibrahim. Angiopoietin-Tie-2 functional axis in colorectal cancer liver metastasis (CRCLM) provides a new marker for stratification and evaluation of tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1825. doi:10.1158/1538-7445.AM2017-1825
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