Differential transplantability of human endothelial cells in colorectal cancer and renal cell carcinoma primary xenografts

Abstract

In vivo models of human tumor vasculature are essential for the study of tumor angiogenesis and validation of therapeutic targets. To date, however, few standardized animal models of human tumor angiogenesis have been characterized. It was recently shown that human renal cell and prostate carcinoma primary xenografts, established from biopsy specimens, contained vessels lined mainly by human endothelial cells 1 month after implantation in immunodeficient mice. We selected colorectal cancer (CRC) as a primary xenograft model and studied the response of the vascular compartment to the new microenvironment during the same lapse of time. Immunohistochemical analysis of the origin of endothelial cells demonstrated that, in contrast to the mentioned study, human endothelial cells were rapidly substituted by their murine counterparts (nearly 50% by day 10 after implantation). Apoptotic human endothelial cells could not be detected 10 days after implantation, suggesting that apoptosis is not the mechanism underlying their replacement. Interestingly, host endothelial cells were found to colocalize with human laminin, suggesting a colonization of human vascular basement membranes after human endothelial cell disappearance. To rule out that the differences observed between the fate of human vasculature in the CRC model and those previously reported were because of methodological aspects, we established renal cell carcinoma (RCC) primary xenografts using the same protocol. In clear contrast with CRC xenografts, vasculature within RCC xenografts was mostly of human origin 35 days after implantation. These results support the notion of angiogenic heterogeneity in malignant neoplasms. Elucidation of the molecular mechanisms that determine persistence or disappearance of human endothelial cells in different tumor contexts can help to shed light on the intimate regulation of the angiogenic process.

Proteomic Characterization of Head and Neck Cancer Patient–Derived Xenografts

“…Characterization of these PDXs so far has focused on genomic and transcriptomic profiling with most studies reporting a general concordance between gene amplification, mutation, and gene expression in the primary and PDX tumor (6, 7). The limitations of PDXs noted to date include evidence that there are molecular and structural changes in PDXs both at early and late passages, particularly noted in endothelial cells (32, 33). Lack of concordance has arisen in some models due to significant intratumoral heterogeneity (31, 34, 35).…”

Human proangiogenic circulating hematopoietic stem and progenitor cells promote tumor growth in an orthotopic melanoma xenograft model

“…AC133 + cells have been associated with poor prognosis in ovarian cancer patients, including shortened overall survival time and non-response to chemotherapy[26]. Furthermore, AC133 + cells have been inversely correlated with glioblastoma, diverse gliomas, breast cancer, colon cancer, and pancreatic patient survival, thus making them an important biomarker in oncology[4,22,27-31]. In the future, identification of specific molecular pathways that promote tumor angiogenesis may be insightful and permit a better understanding of mechanisms that can block tumor angiogenesis and growth.…”

One mouse, one patient paradigm: New avatars of personalized cancer therapy

“…Fourth, several tumors, that are known to metastasize in the patient, do not do so in the PDTX systems thereby severely hampering their applications to guide patient treatment[16]. Fifth, tumor propagation in the mouse may result in several genetic, pathologic, histological and micro-environmental niche changes that may not mirror the patient’s tumor accurately[6,17,18]. Sixth, differential results seen in different immune-deficient mouse strains are another complicating factor.…”