Human xenograft models as useful tools to assess the potential of novel therapeutics in prostate cancer

Weerden, Wytske M. van; Bangma, Chris H.; Wit, Ronald de

doi:10.1038/sj.bjc.6604822

Cited by 51 publications

(44 citation statements)

References 26 publications

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“…The lack of structure within the tumor mass of our xenografts is typical of mouse xenografts [75,76] of prostate cancer. The prostate cancer SCs bear comparison to cancer stem cells from both hematopoietic malignancies and solid tumors.…”

Section: Discussionmentioning

confidence: 91%

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Prostate Cancer Stem Cells: Do They Have a Basal or Luminal Phenotype?

et al. 2011

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The prostate is a luminal secretory tissue whose function is regulated by male sex hormones. Castration produces involution of the prostate to a reversible basal state, and as the majority of prostate cancers also have a luminal phenotype, drug-induced castration is a front line therapy. It has therefore been assumed that the tumor arises from transformation of a luminal progenitor cell. Here, we demonstrate that a minority basal "cancer stem cell" (CSC) population persists in primary human prostate cancers, as in normal prostate, serving as a reservoir for tumor recurrence after castration therapy. While the CSCs exhibit a degree of phenotypic fluidity from different patients, the tumor-initiating cells in immunocompromised mice express basal markers (such as p63), but do not express androgen receptor (AR) or markers of luminal differentiation (PSA, PAP) when freshly fractionated from human tissues or following culture in vitro. Estrogen receptors α and β and AR are transcriptionally active in the transit amplifying (TA) cell (the progeny of SC). However, AR protein is consistently undetectable in TA cells. The prostate-specific TMPRSS2 gene, while upregulated by AR activity in luminal cells, is also transcribed in basal populations, confirming that AR acts as an expression modulator. Selected cells with basal phenotypes are tumor initiating, but the resultant tumors are phenotypically intermediate, with focal expression of AR, AMACR, and p63. In vitro differentiation experiments, employing lentivirally transduced SCs with a luminal (PSA-probasin) promoter regulating a fluorescent indicator gene, confirm that the basal SCs are the source of luminal progeny.

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Section: Discussionmentioning

confidence: 91%

“…However, prostate cancers are notoriously difficult to maintain in cell culture. There are relatively few new convincing cell lines, and those derived from primary xenografts in immunocompromised mice are generally from castration resistant patients' tumors [75,76].…”

Section: Discussionmentioning

confidence: 99%

Prostate Cancer Stem Cells: Do They Have a Basal or Luminal Phenotype?

et al. 2011

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“…This finding likely reflects continued tumor evolution and genotoxic stress over numerous population doublings or further selective pressure to adapt to a murine host. However, these xenografts are able to recapitulate many aspects of prostate cancer in vivo (36,37). Thus, defining the genetic landscapes of these tumors allows one to use the xenografts as a means to test the consequences of mutation functionally and to evaluate therapeutics directed against pathways that are disrupted by specific genetic lesions.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we describe the application of whole-exome sequencing (9) to determine the mutational landscape of 23 prostate cancers representing aggressive and lethal disease, including both metastases and primary carcinomas. All tumors were propagated in immunocompromised mice as tumor xenografts (10) to model the heterogeneity in tumor growth, response to treatment, and lethality that exists in prostate cancer. Furthermore, these tumor xenografts have the advantage of little to no human stromal contamination and provide the means to test the consequences of mutations functionally.…”

mentioning

confidence: 99%

Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers

Kumar

White

MacKenzie

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

236

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To catalog protein-altering mutations that may drive the development of prostate cancers and their progression to metastatic disease systematically, we performed whole-exome sequencing of 23 prostate cancers derived from 16 different lethal metastatic tumors and three high-grade primary carcinomas. All tumors were propagated in mice as xenografts, designated the LuCaP series, to model phenotypic variation, such as responses to cancer-directed therapeutics. Although corresponding normal tissue was not available for most tumors, we were able to take advantage of increasingly deep catalogs of human genetic variation to remove most germline variants. On average, each tumor genome contained ∼200 novel nonsynonymous variants, of which the vast majority was specific to individual carcinomas. A subset of genes was recurrently altered across tumors derived from different individuals, including TP53, DLK2, GPC6, and SDF4. Unexpectedly, three prostate cancer genomes exhibited substantially higher mutation frequencies, with 2,000-4,000 novel coding variants per exome. A comparison of castration-resistant and castration-sensitive pairs of tumor lines derived from the same prostate cancer highlights mutations in the Wnt pathway as potentially contributing to the development of castration resistance. Collectively, our results indicate that point mutations arising in coding regions of advanced prostate cancers are common but, with notable exceptions, very few genes are mutated in a substantial fraction of tumors. We also report a previously undescribed subtype of prostate cancers exhibiting "hypermutated" genomes, with potential implications for resistance to cancer therapeutics. Our results also suggest that increasingly deep catalogs of human germline variation may challenge the necessity of sequencing matched tumornormal pairs.

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“…Furthermore, the widely used LNCaP line has a mutated AR, which results in the receptor also being sensitive to estrogen and progesterone. This mutation has only been identified in a small sub-set of patients, thus making it difficult to generalise the findings with this cell line to hormonal manipulation of prostate cancer [18,19].…”

Section: Immortalised Cell Linesmentioning

confidence: 97%