Since the physiological in vivo environment, although from a different species, mimics the original tumor conditions much better than a plastic dish, success rates of establishing PDTX are higher than for cell lines and genetic divergence is less common [ 15]. Importantly, biological stability of PDTX from a variety of primary tumors including colon, lung, breast, pancreas, prostate, and ovarian cancer has been established [ 16 and 17]. Xenografted colon tumors, for example, preserve their original genetic and histological profiles for up

to 14 passages [ 18]. In addition, several sub-clones grow in parallel and partially conserve parental tumor heterogeneity ( Figure 1). These benefits make PDTX a valid preclinical AG-014699 chemical structure model and allow meaningful biological assays including drug efficacy and predictive biomarker development studies

[ 17]. To this end, PDTX have been used to functionally verify rationally predicted drug response scores [ 19], develop predictive biomarkers for standard and novel anticancer drugs [ 17], and identify effective treatment regimens for patients [ 20••]. Even though PDTX bear great promise as preclinical model for human cancer, there are several caveats. First, tumor take is unsatisfactory with aggressive tumors engrafting best. In some instances, the ability to xenograft even serves as a negative predictor

of the patients’ Selleck Ku-0059436 disease free survival [21]. Second, although similarities between PDTX and parental tumors are common, they cannot be assumed and must be rigorously tested [17]. Third, tumor-host interactions are not always Vasopressin Receptor conserved across species (e.g. HGF-MET) and tumor immunity is entirely absent [3]. Fourth, the use of animals is labor intense, time consuming, and ethically problematic. Consequently, PDTX are no substitute for in vitro cultures with respect to initial high throughput drug screens. This is particularly relevant since altered signaling pathways often crosstalk to others which requires combinatorial therapy of many drug candidates for optimal treatment [ 22]. Recently established organoid cultures from primary tumors [ 23••] may expand the repertoire of available preclinical tumor models by bridging this gap between cancer cell lines and xenografts. The past years have seen unprecedented developments in the use of human tissue surrogates in vitro. Adult stem cells are embedded in a three-dimensional matrix and allowed to self-organize into epithelia of the respective organ of origin. The resulting organoids represent the physiology of native epithelia much better than traditional cell lines. Mini-guts, for example, reproduce the epithelial architecture of small intestine and colon [ 23•• and 24•].