Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.

Fibroblasts in cancer

The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.

Cancer genes and the pathways they control.

ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.

http://basicmed.med.ncku.edu.tw/admin/up_img/990319-2.pdf

Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling

Solid tumours are an enormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumours are hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for the CSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, although alternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains a fundamental issue but preliminary findings indicate that specific targeting may be possible.

Cancer stem cells in solid tumours: accumulating evidence and unresolved questions

The study of normal breast epithelial morphogenesis and carcinogenesis in vivo has largely used rodent models. Efforts at studying mammary morphogenesis and cancer with xenotransplanted human epithelial cells have failed to recapitulate the full extent of development seen in the human breast. We have developed an orthotopic xenograft model in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin. Genetic modification of human stromal cells before the implantation of ostensibly normal human mammary epithelial cells resulted in the outgrowth of benign and malignant lesions. This experimental model allows for studies of human epithelial morphogenesis and differentiation in vivo and underscores the critical role of heterotypic interactions in human breast development and carcinogenesis.

https://www.pnas.org/content/pnas/101/14/4966.full.pdf

Reconstruction of functionally normal and malignant human breast tissues in mice

Breast cancer development is a complex pathobiological process involving sequential genetic alterations in normal epithelial cells that results in uncontrolled growth in a permissive microenvironment. Accordingly, physiologically relevant models of human breast cancer that recapitulate these events are needed to study cancer biology and evaluate therapeutic agents. Here, we report the generation and utilization of the human breast cancer in mouse (HIM) model, which is composed of genetically engineered primary human breast epithelial organoids and activated human breast stromal cells. By using this approach, we have defined key genetic events required to drive the development of human preneoplastic lesions as well as invasive adenocarcinomas that are histologically similar to those in patients. Tumor development in the HIM model proceeds through defined histological stages of hyperplasia, DCIS to invasive carcinoma. Moreover, HIM tumors display characteristic responses to targeted therapies, such as HER2 inhibitors, further validating the utility of these models in preclinical compound testing. The HIM model is an experimentally tractable human in vivo system that holds great potential for advancing our basic understanding of cancer biology and for the discovery and testing of targeted therapies.

https://www.pnas.org/content/pnas/106/17/7022.full.pdf

Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice

A reconstituted human breast tumor model is disclosed. The model, which is incorporated into mice, provides actual tumors that arise spontaneously, thereby mimicking naturally occurring breast cancer. The tumors are genetically human, because they arise from human mammary tissues that develop from human mammary epithelial cells implanted into host mice. Prior to implantation, the mammary epithelial cells are genetically modified to contain a recombinant human oncogene and an SV40 early region.

Reconstituted human breast tumor model

Animal models for cancer research, although not perfect, have traditionally been crucial to the drug discovery and development process. Recent advances in genetically modified mice have created opportunities to model many aspects of cancer biology, which established xenograft models ignore. Selection of the right model will be of increasing importance in the search for efficacious human therapeutics. These improved mouse models also permit a new concept of preclinical trials in which the efficacy of novel drugs can be tested against spontaneous tumors.

Genetically Engineered Mouse Models of Human Cancer for Drug Discovery and Development

Comment on: Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice. Wu M, et al. Proc Natl Acad Sci USA 2009; 106:7022-7.

Min Wu

Papers

Reconstruction of functionally normal and malignant human breast tissues in mice

Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice

Reconstituted human breast tumor model

Genetically Engineered Mouse Models of Human Cancer for Drug Discovery and Development

Human-in-mouse breast cancer model.