Rogers M.S.,Boston Childrens Hospital |
Rogers M.S.,Harvard University |
Novak K.,Boston Childrens Hospital |
Cryan L.M.,Boston Childrens Hospital |
And 21 more authors.
Molecular Cancer Research | Year: 2014
The angiogenic switch, a rate-limiting step in tumor progression, has already occurred by the time most human tumors are detectable. However, despite significant study of the mechanisms controlling this switch, the kinetics and reversibility of the process have not been explored. The stability of the angiogenic phenotype was examined using an established human liposarcoma xenograft model. Nonangiogenic cells inoculated into immunocompromised mice formed microscopic tumors that remained dormant for approximately 125 days (vs. <40 days for angiogenic cells) whereupon the vast majority (>95%) initiated angiogenic growth with second-order kinetics. These original, clonally derived angiogenic tumor cells were passaged through four in vivo cycles. At each cycle, a new set of single-cell clones was established from the most angiogenic clone and characterized for in vivo for tumorigenic activity. A total of 132 single-cell clones were tested in the second, third, and fourth in vivo passage. Strikingly, at each passage, a portion of the single-cell clones formed microscopic, dormant tumors. Following dormancy, like the original cell line, these revertant tumors spontaneously switched to the angiogenic phenotype. Finally, revertant clones were transcriptionally profiled and their angiogenic output determined. Collectively, these data demonstrate that the angiogenic phenotype in tumors is malleable and can spontaneously revert to the nonangiogenic phenotype in a population of human tumor cells. © 2014 American Association for Cancer Research.
Schulz J.-N.,University of Cologne |
Zeltz C.,Center for Cancer Biomarkers |
Sorensen I.W.,Center for Cancer Biomarkers |
Barczyk M.,Center for Cancer Biomarkers |
And 6 more authors.
Journal of Investigative Dermatology | Year: 2015
Previous wound healing studies have failed to define a role for either α1β1 or α2β1 integrin in fibroblast-mediated wound contraction, suggesting the involvement of another collagen receptor in this process. Our previous work demonstrated that the integrin subunit α11 is highly induced during wound healing both at the mRNA and protein level, prompting us to investigate and dissect the role of the integrin α11β1 during this process. Therefore, we used mice with a global ablation of either α2 or α11 or both integrin subunits and investigated the repair of excisional wounds. Analyses of wounds demonstrated that α11β1 deficiency results in reduced granulation tissue formation and impaired wound contraction, independently of the presence of α2β1. Our combined in vivo and in vitro data further demonstrate that dermal fibroblasts lacking α11β1 are unable to efficiently convert to myofibroblasts, resulting in scar tissue with compromised tensile strength. Moreover, we suggest that the reduced stability of the scar is a consequence of poor collagen remodeling in α11 -/- wounds associated with defective transforming growth factor-β-dependent JNK signaling. © 2015 The Society for Investigative Dermatology.
Blanchard A.,University of Bergen |
Blanchard A.,Center for Cancer Biomarkers
New Biotechnology | Year: 2016
Cancer biomarkers represent a revolutionary advance toward personalised cancer treatment, promising therapies that are tailored to subgroups of patients sharing similar generic traits. Notwithstanding the optimism driving this development, biomarkers also present an array of social and ethical questions, as witnessed in sporadic debates across different literatures. This review article seeks to consolidate these debates in a mapping of the complex terrain of ethical and social aspects of cancer biomarker research. This mapping was undertaken from the vantage point offered by a working cancer biomarker research centre called the Centre for Cancer Biomarkers (CCBIO) in Norway, according to a dialectic move between the literature and discussions with researchers and practitioners in the laboratory. Starting in the lab, we found that, with the exception of some classical bioethical dilemmas, researchers regarded many issues relative to the ethos of the biomarker community; how the complexity and uncertainty characterising biomarker research influence their scientific norms of quality. Such challenges to the ethos of cancer research remain largely implicit, outside the scope of formal bioethical enquiry, yet form the basis for other social and ethical issues. Indeed, looking out from the lab we see how questions of complexity, uncertainty and quality contribute to debates around social and global justice; undermining policies for the prioritisation of care, framing the stratification of those patients worthy of treatment, and limiting global access to this highly sophisticated research. We go on to discuss biomarker research within the culturally-constructed ‘war on cancer’ and highlight an important tension between the expectations of ‘magic bullets’ and the complexity and uncertainty faced in the lab. We conclude by arguing, with researchers in the CCBIO, for greater reflexivity and humility in cancer biomarker research and policy. © 2016 The Author
Stuhr L.E.B.,University of Bergen |
Stuhr L.E.B.,Center for Cancer Biomarkers |
Wei E.T.,University of California at Berkeley |
Reed R.K.,University of Bergen |
Reed R.K.,Center for Cancer Biomarkers
Tumor Biology | Year: 2014
The present study examines the effect of the endogenous neuroendoccrine factor, corticotropin-releasing factor (CRF), alone or in combination with 5-fluorouracil (5-FU), on 4T1 mammary tumor cells in vitro and in vivo. CRF has been detected in breast cancer tissues; however, the biological effects reported in the literature are sparse and variable. We found that exogenously administered CRF significantly reduced tumor growth without influencing angiogenesis or cell death. Furthermore, CRF reduced tumor interstitial fluid pressure (Pif) and potentiated the effect of 5-FU. These results show that CRF has antitumor effect on mammary carcinoma in mice. © International Society of Oncology and BioMarkers (ISOBM) 2013.
Mauland K.K.,University of Bergen |
Wik E.,Center for Cancer Biomarkers |
Wik E.,University of Bergen |
Salvesen H.B.,University of Bergen
Cytometry Part B - Clinical Cytometry | Year: 2014
Endometrial carcinoma (EC) is the most common gynecologic cancer in industrialized countries. Traditional prognostic markers include FIGO stage, histologic subtype, and histologic grade. DNA ploidy was introduced as a prognostic marker 30 years ago, and the majority of published literature demonstrates significant associations between tumor aneuploidy and poorer prognosis in EC. However, ploidy analysis is not routinely implemented in the clinic. We reviewed the literature on clinical value of ploidy measured by DNA content as a prognostic marker, and its potential role as a predictive marker in EC. PubMed was searched for papers evaluating the prognostic or predictive role of ploidy in EC. Search criteria were "DNA ploidy prognosis/predictive value endometrial cancer/carcinoma". Only articles written in English, published year 2000 or later were included. The majority of the studies demonstrated highly significant correlation between DNA index (DI) and survival, in univariate analysis including stages I-IV, and in subgroup analysis of stage I and stage I-II EC. Several studies also showed significant association between DI and survival in multivariate analysis. Few studies have evaluated DI as a prognostic marker in a prospective setting. No studies evaluating DI as a predictive marker in EC were identified. In other cancer types, ploidy has been linked to prediction of response to hormonal therapy and chemotherapy. Ploidy assessment in EC by DI is a strong prognostic marker. Still, its clinical applicability needs validation in a routine diagnostic, prospective setting with sufficient number of patients, characterized by state of the art histopathological evaluation and surgical staging. © 2014 International Clinical Cytometry Society © 2014 Clinical Cytometry Society.