Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow–derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow–derived EPC in a vascular endothelial growth factor–dependent and stromal-derived factor 1–dependent manner.
Vascular endothelial cells have been identified as a critical component of the neural stem cell niche, raising the possibility that brain tumor stem-like cells (TSLC) may also rely on signaling interactions with nearby tumor vasculature to maintain their stem-like state. The disruption of such a TSLC vascular niche by an antiangiogenic therapy could result in loss of stemness characteristics associated with intrinsic drug resistance and, thus, preferentially sensitize TSLC to the effects of chemotherapy. Considering these possibilities, we investigated the impact of antiangiogenic anticancer therapy on the TSLC fraction of glioma tumors. Athymic nude mice bearing s.c. tumor xenografts of the C6 rat glioma cell line were treated with either a targeted antiangiogenic agent, antiangiogenic schedules of low-dose metronomic chemotherapy, combination therapies of antiangiogenic agents and chemotherapy, or, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose chemotherapy using cyclophosphamide. Targeted antiangiogenic therapy or cytotoxic chemotherapy did not reduce the fraction of tumor sphere-forming units (SFU) in the tumor, whereas all treatment groups that combined both antiangiogenic and cytotoxic drug effects caused a significant reduction in SFU. This work highlights the possibility that selective eradication of TSLC may be achieved by targeting the tumor microenvironment (and potentially a supportive TSLC niche) rather than the TSLC directly. Furthermore, this work suggests a possible novel effect of antiangiogenic therapy, namely, as a chemosensitizer of TSLC, and thus represents a possible new mechanism to explain the ability of antiangiogenic therapy to enhance the efficacy of chemotherapy. [Cancer Res 2007;67(8):3560-4]
Canadian provinces routinely collect patient-level data for administrative purposes. These real-world data (RWD) can be used to generate real-world evidence (RWE) to inform clinical care and healthcare policy. The CanREValue Collaboration is developing a framework for the use of RWE in cancer drug funding decisions. A Data Working Group (WG) was established to identify data assets across Canada for generating RWE of oncology drugs. The mapping exercise was conducted using an iterative scan with informant surveys and teleconference. Data experts from ten provinces convened for a total of three teleconferences and two in-person meetings from March 2018 to September 2019. Following each meeting, surveys were developed and shared with the data experts which focused on identifying databases and data elements, as well as a feasibility assessment of conducting RWE studies using existing data elements and resources. Survey responses were compiled into an interim data report, which was used for public stakeholder consultation. The feedback from the public consultation was used to update the interim data report. We found that databases required to conduct real-world studies are often held by multiple different data custodians. Ninety-seven databases were identified across Canada. Provinces held on average 9 distinct databases (range: 8–11). An Essential RWD Table was compiled that contains data elements that are necessary, at a minimal, to conduct an RWE study. An Expanded RWD Table that contains a more comprehensive list of potentially relevant data elements was also compiled and the availabilities of these data elements were mapped. While most provinces have data on patient demographics (e.g., age, sex) and cancer-related variables (e.g., morphology, topography), the availability and linkability of data on cancer treatment, clinical characteristics (e.g., morphology and topography), and drug costs vary among provinces. Based on current resources, data availability, and access processes, data experts in most provinces noted that more than 12 months would be required to complete an RWE study. The CanREValue Collaboration’s Data WG identified key data holdings, access considerations, as well as gaps in oncology treatment-specific data. This data catalogue can be used to facilitate future oncology-specific RWE analyses across Canada.
Background Characterizing the prevalence and distribution of frailty within a population can help guide decision-making and policy development by identifying health service resource needs. Here we describe the prevalence of frailty among hospitalized older adults in New Brunswick (NB), Canada. Methods NB administrative hospital claims data were used to identify hospitalized older adults aged 65 or older between April 1, 2017 and March 31, 2019. Frailty was quantified using the Hospital Frailty Risk Score (HFRS), a validated frailty tool derived from claims data. Individuals with a HFRS ranked as intermediate or high were categorized as frail. The distribution of frailty across sex and age are described. Crude prevalence estimates and corresponding 95% confidence intervals are presented. Results A total of 55,675 older adults (52% females) were hospitalized. The overall prevalence of frailty was 21.2% (95%CI: 20.9–21.6). Prevalence increased with age: 12.7% (95%CI: 12.3–13.1) in the 65–74 age group, 24.7% (95%CI: 24.1–25.3) in the 75–84 age group and 41.6% (95%CI: 40.6–42.7) for those aged 85 and over (p<.001). Discussion/Conclusion The distribution of frailty is in line with that reported in other jurisdictions. We demonstrate the feasibility of the HFRS to identify and characterize frailty in a large sample of older adults who were hospitalized, using administrative data.
If we understand correctly the arguments outlined by Bonnefoix and Callanan, they are suggesting that the limiting dilution transplantation assay (LDTA) results that we presented do not fit the Single-Hit Poisson Model. Although it is correct that the fact that our LDTA results do not fit the Single-Hit Poisson Model would prevent us from using Poisson statistics to estimate the exact frequency of cancer stem cells in each culture, we see no reason why this would prevent us from drawing a conclusion about the relative tumor initiating capacity in each culture (which, incidentally, was the only direct conclusion we made in our article based on the LDTA). Such a conclusion does not, to our knowledge, assume single-hit statistics, and it still allows for the possibility that tumor initiation by cancer stem cells is not necessarily a single-hit event (which is probably the case, especially in a xenograft assay). Therefore, we think it may be inappropriate to state categorically that any comparison between Ser+ and SFS LDTAs is precluded.
Supplementary Figure Legends 1-2 from Glioma Tumor Stem-Like Cells Promote Tumor Angiogenesis and Vasculogenesis via Vascular Endothelial Growth Factor and Stromal-Derived Factor 1
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