The capacity to induce neoplasia in human tissue in the laboratory has recently provided a new platform for cancer research. Malignant conversion can be achieved in vivo by expressing genes of interest in human tissue that has been regenerated on immune-deficient mice. Induction of cancer in regenerated human skin recapitulates the three-dimensional architecture, tissue polarity, basement membrane structure, extracellular matrix, oncogene signalling and therapeutic target proteins found in intact human skin in vivo. Human-tissue cancer models therefore provide an opportunity to elucidate fundamental cancer mechanisms, to assess the oncogenic potency of mutations associated with specific human cancers and to develop new cancer therapies.
Malignant conversion of human tissue can be achieved rapidly in a three-dimensionally faithful human tissue context that contains primary human cells, epithelial basement-membrane zone and extracellular matrix by using high-efficiency gene transfer and regeneration of human skin on immune-deficient mice.
Human skin tissue can be converted directly into the three most common human skin cancers by introducing as few as one, two or three specific, defined genetic elements that are implicated in the development of these tumours.
Malignant conversion to basal cell carcinoma can be achieved with only one genetic alteration in human skin — overexpression of active sonic hedgehog (SHH).
Lethal squamous-cell carcinoma can be induced in regenerated human skin through the expression of oncogenic HRAS and only one other genetic element that facilitates escape from G1 cell-cycle arrest, including cyclin-dependent kinase 4 (CDK4) or the nuclear factor-κB inhibitor, IκBα.
Induction of human melanocytic neoplasia that is indistinguishable from locally invasive malignant melanoma results from expression of oncogenic NRAS and the catalytic subunit of human telomerase reverse transcriptase (TERT) in combination with either CDK4 or dominant-negative p53.
Human-tissue cancer models indicate that genomic catastrophe and memory-based inflammatory immune responses are not required for epithelial carcinogenesis. These models also indicate that traditional in vitro measures of neoplastic transformation, such as immortalization and anchorage-independent growth on soft agar, might not be reliable surrogate measures of human tissue tumorigenicity in vivo.
The oncogenic potency of specific cancer-associated mutants such as BRAFV600E, the mutant that is most commonly found in malignant melanoma, can be directly tested in human tissue.
Human-tissue cancer models might facilitate the validation of therapeutic interventions against human protein targets in a native human tissue environment. An example of this is the identification of type VII collagen blockade as a strategy to inhibit neoplastic invasion across the cutaneous basement-membrane zone.
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A. Oro, M. P. Marinkovich, E. Epstein, H. Chang, D. Felsher, L. Attardi, J. Sage, S. Artandi, Z. Siprashvili, J. Reuter, P. Dumesic, R. Kimmel, T. Ridky, A. Adams, H. Lee, J. Zhang, J. Chudnovsky, J. Garcia, F. Scholl and S. Ortiz-Urda provided critical pre-submission review and helpful comments. S. Kohler and F. Scholl generously provided histology specimens. This work was supported by the Veterans Affairs Office of Research and Development, and by the NIH/NIAMS.
The author declares no competing financial interests.
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