Desmoids in familial adenomatous polyposis are monoclonal proliferations

Middleton, Simon B.; Frayling, Ian Martin; Phillips, R. K. S.

doi:10.1054/bjoc.1999.1007

Cited by 87 publications

(26 citation statements)

References 34 publications

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“…Normal stroma in the periphery of the cancer biopsy was completely keratinnegative (not shown). The epithelial stromal relationship was further substantiated by the fact that HBFL-1 and laser pressure catapulted carcinoma cells from the tissue of origin were clonal with an identical non-random X-chromosome inactivation pattern (ratio less than 0.5) 30,31 as assessed with the HUMARA clonality assay ( Figure 3C). A rudimentary epithelial phenotype was revealed in the majority of cells also by double staining with antibodies To show a broader evidence that a combined induction of ␣-sm actin and loss of keratin could arise as a consequence of an EMT phenomenon was demonstrated by use of two additional basaloid breast carcinoma cell lines (HMT-3909S1 and HMT-3522T4).…”

Section: Evidence For a Neoplastic Origin Of Hbfl-1mentioning

confidence: 85%

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Epithelial to Mesenchymal Transition in Human Breast Cancer Can Provide a Nonmalignant Stroma

Petersen¹,

Nielsen²,

Gudjonsson³

et al. 2003

The American Journal of Pathology

266

196

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A breast carcinoma biopsy showed cytochemical evidence of epithelial mesenchymal transition and an ␣-smooth muscle actin-positive stromal reaction. To study the lineage, and the nature of the cells in the stromal reaction, we derived a novel cell line, HBFL-1, from the explanted biopsy. HBFL-1 cells are immortal and exhibit a shared non-random X-chromosome inactivation pattern with the epithelial tumor of origin. Yet they closely resemble normal, finite-life-span fibroblasts by morphology, lack of tumor formation in nude mice, marker expression profile, protein pattern using two-dimensional gel electrophoresis and the ability to undergo myofibroblast conversion. HBFL-1 interacts reciprocally with tumor cells in collagen gel to induce activation of MMP2, leading to tumor-like behavior of epithelial colonies. In vivo, HBFL-1 cells resembled normal-derived myofibroblasts and conferred a significant 3.5-to 7-fold increase in MCF-7 tumor size in nude mice. However, that they were indeed not normal fibroblasts was revealed by residual keratin expression and formation of epithelial microfoci in a reconstituted basement membrane and in nude mice. We conclude that breast cancer can generate its own nonmalignant stroma and that one function for this is that of a reciprocal interac- Epithelial mesenchymal transition (EMT) was originally described as a normal developmental process. 1,2 Later, it was adopted as an explanation for mesenchymal conversion in a number of cultured epithelial cells. 3,4 In cancer, EMT generally depicts a more aggressive behavior of the tumor cells. 5,6 In breast cancer, EMT has been estimated to occur in as much as 18% of tumors in vivo. [7][8][9] Under these conditions EMT is defined as the occurrence of a variable proportion of tumor cells that express mesenchymal markers such as vimentin, tenascin and stromelysin-3. 7,10 In its most elaborate form, EMT-derived cells of mixed epithelial-mesenchymal breast tumors may be difficult to distinguish from resident normal stromal cells. 11 These tumors which are also referred to as carcinosarcomas or metaplastic carcinomas in particular offer an excellent opportunity to study the nature and the consequence of this subset of EMT. 5,6 Such studies, however, have been hampered by lack of representative cell lines most likely due to low frequency of overtly metaplastic carcinomas but also to difficulties in culturing breast cancer cells in general. In the present study we succeeded in isolating a mesenchymal-like cell line from a metaplastic human breast carcinoma. Clonality analysis revealed that the cell line and the epithelial tumor cells of origin had a common ancestor. Even though the cells were immortal and severely aneuploid, and exhibited a rudimentary epithelial phenotype in terms of keratin expression and formation of microfoci in Matrigel and in vivo, they nevertheless behaved remarkably like normal resident fibroblasts. In particular they responded to transforming growth factor-␤ (TGF-␤) by having ␣-smooth muscle actin (␣-sm actin) induced and t...

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Section: Evidence For a Neoplastic Origin Of Hbfl-1mentioning

confidence: 85%

“…Clonality ratios were calculated according to Willman et al, 29 and a clonal ratio of less than 0.5 was considered indicative of a clonal composition. 30,31 …”

Section: Human Androgen Receptor (Humara) Clonality Assaymentioning

confidence: 99%

Epithelial to Mesenchymal Transition in Human Breast Cancer Can Provide a Nonmalignant Stroma

Petersen¹,

Nielsen²,

Gudjonsson³

et al. 2003

The American Journal of Pathology

266

196

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“…Cells were seeded in culture medium without antibiotics at a cell density of 10 4 per cm 2 . The following day, the cells were transfected for 4 hours with Oligofectamine reagent (Invitrogen) combined with siRNAs at a concentration of 300 nmol/L in reduced serum medium Opti-MEM I (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…Desmoid tumors are locally aggressive monoclonal proliferations of fibroblast-like cells (1,2). Their cortex is highly vascularized and surgical resection is suspected to induce recurrence of the tumor (3).…”

Section: Introductionmentioning

confidence: 99%

Assessment of Endostatin Gene Therapy for Familial Adenomatous Polyposis–Related Desmoid Tumors

et al. 2006

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Constitutive activation of the Wnt signaling pathway is a hallmark of many cancers, including familial adenomatous polyposis (FAP)-related desmoid tumors. Endostatin is a wellknown antiangiogenic protein that has been described recently as a potential inhibitor of this signaling pathway. Here, we show that endostatin directly induces apoptosis and inhibits the Wnt signaling pathway in colorectal cancer cell lines bearing mutations on the adenomatous polyposis coli (APC) gene as a model of FAP-related malignant cells. We then explore the relationship between apoptosis and inhibition of this pathway and show that they are not correlated. These results seem to contradict a well-recognized study, showing that reintroduction of the APC cDNA in APC-deficient cells leads to apoptosis. To reconcile our conclusions with the literature, we further show that a truncated fragment of APC capable of inhibiting the Wnt signaling pathway in SW480 cells is incapable of inducing apoptosis in these cells, confirming that APC-mediated apoptosis is uncoupled to the inhibition of the Wnt signaling pathway. Finally, we show that endostatin directly induces cell death on primary FAP-related desmoid tumor cells in culture. This phenomenon is also independent of the inhibition of the Wnt signaling pathway. Considering the current lack of effective treatment against desmoid tumors, we advocate that endostatin gene therapy represents an attractive new therapeutic approach for this disease. (Cancer Res 2006; 66(16): 8233-40)

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“…While recruited stem/progenitor cells undergo terminal differentiation or apoptosis during the resolution phase of normal wound healing, under conditions of chronic inflammation or tumor progression, these activated cells persist (79). A synergistic cooperation of these multipotent cells support angiogenesis, a hallmark of accelerated wound healing and fibrosis (33,80). Increased angiogenesis and proliferation of fibroblast-like cells within a collagen matrix are features of desmoids as well (33).…”

Section: Desmoid Etiology and Wound Healingmentioning

confidence: 99%

Diagnosis and multidisciplinary treatment of sporadical desmoid tumors

Mátrai¹

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Desmoids in familial adenomatous polyposis are monoclonal proliferations

Cited by 87 publications

References 34 publications

Epithelial to Mesenchymal Transition in Human Breast Cancer Can Provide a Nonmalignant Stroma

Epithelial to Mesenchymal Transition in Human Breast Cancer Can Provide a Nonmalignant Stroma

Assessment of Endostatin Gene Therapy for Familial Adenomatous Polyposis–Related Desmoid Tumors

Diagnosis and multidisciplinary treatment of sporadical desmoid tumors

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