[Show abstract][Hide abstract] ABSTRACT: Background:
Extracellular vesicles released by prostate cancer present in seminal fluid, urine, and blood may represent a non-invasive means to identify and prioritize patients with intermediate risk and high risk of prostate cancer. We hypothesize that enumeration of circulating prostate microparticles (PMPs), a type of extracellular vesicle (EV), can identify patients with Gleason Score≥4+4 prostate cancer (PCa) in a manner independent of PSA.
Patients and methods:
Plasmas from healthy volunteers, benign prostatic hyperplasia patients, and PCa patients with various Gleason score patterns were analyzed for PMPs. We used nanoscale flow cytometry to enumerate PMPs which were defined as submicron events (100-1000nm) immunoreactive to anti-PSMA mAb when compared to isotype control labeled samples. Levels of PMPs (counts/µL of plasma) were also compared to CellSearch CTC Subclasses in various PCa metastatic disease subtypes (treatment naïve, castration resistant prostate cancer) and in serially collected plasma sets from patients undergoing radical prostatectomy.
PMP levels in plasma as enumerated by nanoscale flow cytometry are effective in distinguishing PCa patients with Gleason Score≥8 disease, a high-risk prognostic factor, from patients with Gleason Score≤7 PCa, which carries an intermediate risk of PCa recurrence. PMP levels were independent of PSA and significantly decreased after surgical resection of the prostate, demonstrating its prognostic potential for clinical follow-up. CTC subclasses did not decrease after prostatectomy and were not effective in distinguishing localized PCa patients from metastatic PCa patients.
PMP enumeration was able to identify patients with Gleason Score ≥8 PCa but not patients with Gleason Score 4+3 PCa, but offers greater confidence than CTC counts in identifying patients with metastatic prostate cancer. CTC Subclass analysis was also not effective for post-prostatectomy follow up and for distinguishing metastatic PCa and localized PCa patients. Nanoscale flow cytometry of PMPs presents an emerging biomarker platform for various stages of prostate cancer.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Small animal immobilization devices facilitate positioning of animals for reproducible imaging and accurate focal radiation therapy. In this study, the authors demonstrate the use of three-dimensional
(3D) printing technology to fabricate a custom-designed mouse head restraint. The authors evaluate the accuracy of this device for the purpose of mouse brain irradiation.
[Show abstract][Hide abstract] ABSTRACT: Osteopontin (OPN), a malignancy-associated secreted phosphoprotein, is a prognostic plasma biomarker for survival in metastatic breast cancer patients. We evaluated the role of OPN in Locally Advanced Breast Cancer (LABC) patients in predicting response to neoadjuvant chemotherapy and association with survival. Fifty-three patients with non-metastatic LABC were enrolled in this study and monitored serially for plasma OPN levels by ELISA during neoadjuvant chemotherapy prior to surgery. For fifty patients who had baseline OPN levels available for analysis, the median baseline OPN level was 63.6 ng/ml. Median patient follow up was 45 months and thirteen patients died from metastatic disease. Patients with baseline OPN levels ≥ 63.6 ng/ml were significantly more likely to die of their disease than those with baseline OPN < 63.6 ng/mL (Hazard Ratio = 3.4; 95% confidence interval 1.4-11.3; P = 0.011), and overall, baseline OPN level was significantly associated with survival (P = 0.002). There was little support for value of serial OPN determination in monitoring response to therapy in this patient population. Although the percentage of patients with baseline OPN levels < 63.6 ng/ml was higher in patients with pathological complete response than in those with no response, the difference was not statistically significant (64% and 14%, respectively (P = 0.066)). Thus, baseline plasma OPN level is a prognostic biomarker in this group of LABC patients, and could also be helpful in identifying LABC patients who will respond to neoadjuvant chemotherapy. Our results call for validation of our findings in large prospective trial data sets.
No preview · Article · Jun 2015 · American Journal of Translational Research
[Show abstract][Hide abstract] ABSTRACT: IntroductionMost cancer deaths are due to metastasis—the spread of cancer from its site of origin to distant, vital organs—and the physiological damage caused by tumor growth in those organs. While the broad outlines of the process of metastatic spread are known, much of the details of the process remain poorly understood. To continue to improve cancer survival rates, we must face and tackle the problems inherent to metastatic disease. Cancers that are detected early, before they are believed to have spread to other organs, are generally treated with more success than cancers that are metastatic at diagnosis. However, even cancers that are detected early will recur in some patients, but our ability to predict which individuals will have recurrences is limited. Thus, adjuvant therapy is often given to patients with early-stage disease who are believed as a group to be at risk for recurrence, leading to overtreatment of some patients to benefit a subset of them and possibly failing to tr ...
No preview · Article · Mar 2015 · Journal of Molecular Medicine
[Show abstract][Hide abstract] ABSTRACT: Due to the high level of heterogeneity and mutations inherent in human cancers, single agent therapies, or combination regimens which target the same pathway, are likely to fail. Emphasis must be placed upon the inhibition of pathways that are responsible for intrinsic and/or adaptive resistance to therapy. An active field of investigation is the development and testing of DNA repair inhibitors that promote the action of, and prevent resistance to, commonly used chemotherapy and radiotherapy. We used a novel protocol to evaluate the effectiveness of BRCA2 inhibition as a means to sensitize tumor cells to the DNA damaging drug cisplatin. Tumor cell metabolism (acidification and respiration) was monitored in real-time for a period of 72 hr to delineate treatment effectiveness on a minute by minute basis. In combination, we performed an assessment of metastatic frequency using a chicken embryo chorioallantoic membrane (CAM) model of extravasation and invasion. This protocol addresses some of the weaknesses of commonly used in vitro and in vivo methods to evaluate novel cancer therapy regimens. It can be used in addition to common methods such as cell proliferation assays, cell death assays, and in vivo murine xenograft studies, to more closely discriminate amongst candidate targets and agents, and select only the most promising candidates for further development.
Full-text · Article · Feb 2015 · Journal of Visualized Experiments
[Show abstract][Hide abstract] ABSTRACT: Tumor-derived matricellular proteins such as osteopontin (OPN) and tenascin-C (TN-C) have been implicated in tumor growth and metastasis. However, the molecular basis of how these proteins contribute to tumor progression remains to be elucidated. Importantly, these matricellular proteins are known to interact with alpha 9 beta 1 integrin. Therefore, we hypothesized that tumor-derived alpha 9 beta 1 integrin may contribute to tumor progression. To clarify the roles of alpha 9 beta 1 integrin in tumor growth and lymphatic metastasis, we used an inhibitory anti-human alpha 9 beta 1 integrin antibody (anti-h alpha 9 beta 1 antibody) and a alpha 9 beta 1 integrin-positive human breast cancer cell line, MDA-MB-231 luc-D3H2LN (D3H2LN), in vitro functional assays, and an in vivo orthotopic xenotransplantation model. In this study, we demonstrated that tumor, but not host alpha 9 beta 1 integrin, contributes to tumor growth, lymphatic metastasis, recruitment of cancer-associated fibroblasts (CAFs), and host-derived OPN production. We also found that CAFs contributed to tumor growth, lymphatic metastasis, and host-derived OPN levels. Consistent with those findings, tumor volume was well-correlated with numbers of CAFs and levels of host-derived OPN. Furthermore, it was shown that the inoculation of D3H2LN cells into mammary fat pads with mouse embryonic fibroblasts (MEFs), obtained from wild type, but not OPN knock-out mice, resulted in enhancement of tumor growth, thus indicating that CAF-derived OPN enhanced tumor growth. These results suggested that tumor alpha 9 beta 1-mediated signaling plays a pivotal role in generating unique primary tumor tissue microenvironments, which favor lymphatic metastasis and tumor growth.
Full-text · Article · Jan 2015 · Journal of Molecular Medicine
[Show abstract][Hide abstract] ABSTRACT: The effective treatment of metastatic cancer is complicated by both the diverse set of dysregulated molecular pathways contributing to cancer progression and the challenge of aiming clinical therapies at a seemingly unpredictable moving target. From an evolutionary perspective, metastasis can be considered as a process during which novel cell populations are generated that can exploit the unique tissue environments they encounter at a secondary tissue site and in response to treatment. In this review, we explore metastasis as a consequence of evolution on the scale of tumor cells within the individual patient. The survivability of any individual cancer cell, and as a consequence, the success of any broad-based or targeted therapy to treat that patient, may best be understood in terms of selective advantage and phenotypic changes resulting from genomic drift among cells from the original tumor. These drivers of evolution can generate successful metastatic cells that either survive as dormant cells, or thrive as secondary tumors during the time course of the disease. The metastatic target is thus dynamic, requiring a dynamic approach to treatment. Here we will discuss the growing information about heterogeneity and evolution of metastatic cell populations, and how this information impacts on treatment strategies that will be needed to combat metastatic disease.
[Show abstract][Hide abstract] ABSTRACT: Operator-dependent settings such as the wall filter cut-off frequency control the incidence of artifacts in Doppler images and limit the reliability of comparisons of Doppler vascular indices across longitudinal studies. To address this problem, the wall filter selection curve (WFSC) method was developed to objectively select the cut-off frequency. This paper reports the first evaluation of the effectiveness of the WFSC method for imaging a tumor model. 3-D power Doppler data were acquired from murine breast cancer tumors over a six-week study and the WFSC method was applied to select a cut-off frequency for the wall filter. Images reconstructed using the WFSC method were compared to images processed using a fixed cut-off frequency. Selection curves for tumor images were consistent with flow-phantom data from previous studies. The mean WFSC-selected cut-off showed significant variation among images acquired at different time points from each tumor (two-way ANOVA, p < 0.0001), which demonstrates the relevance of adjusting the cut-off frequency to match changing flow conditions. 3-D images processed using the WFSC method depicted additional vascular structures compared to volumes processed using a fixed cut-off frequency. Therefore, the WFSC method can facilitate acquisition of reliable Doppler images by inexperienced or time-sensitive operators.
[Show abstract][Hide abstract] ABSTRACT: Biomedical Imaging Research Center (BIRC) in London, Ontario, Canada.
The BIRC is internationally known for its research. The prostate cancer team from the BIRC has developped the 18F-fluorocholine, a new tracer for prostate cancer imaging.
The Dean's Awards of Excellence for Faculty was obtained by the BIRC team in 2014.
Schulich School of Medicine & Dentistry : http://www.schulich.uwo.ca/about/news/2014/april/congratulations_to_the_2014_awards_of_excellence_recipients.html