TGFβ1 Inhibits the Formation of Benign Skin Tumors, but Enhances Progression to Invasive Spindle Carcinomas in Transgenic Mice

Cui, Wei; Fowlis, Deborah; Bryson, Sheila; Duffie, Elizabeth; Ireland, H. Elyse; Balmain, Allan; Akhurst, Rosemary J.

doi:10.1016/s0092-8674(00)80127-0

Cited by 586 publications

(451 citation statements)

References 65 publications

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“…TGF-b1 expression and endogeneous type II TGF-b receptor expression was present in the majority of early carcinomas derived from our dominant negative type II receptor transgenic mice. These results suggests that the carcinomas pro®t from tumor stimulating activities of TGF-b on stroma and angiogenesis (Roberts et al, 1986;FuÈ rstenberger et al, 1989;Cui et al, 1996;Oft et al, 1996). The malignant cells escape TGF-b mediated growth restriction due to the presence of the dominant negative type II receptor allowing for a very rapid growth of these lesions.…”

Section: Discussionmentioning

confidence: 93%

“…Therefore, it has been suggested that TGF-b plays an important role in skin carcinogenesis (Glick et Glick et al, 1994;Cui et al, 1996). To elucidate the function of TGF-b signaling in tumor development we subjected our transgenic mice to skin carcinogenesis protocols (DiGiovanni, 1991;Hennings et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, loss of TGF-b expression in benign skin papillomas is correlated with a high risk for malignant conversion (Missero et al, 1991;Glick et al, 1993;Cui et al, 1994;Glick et al, 1994). On the other hand, TGF-b can also stimulate malignant progression, possibly by its action on cell-matrix interaction, by its immunosuppressive activities or by enhancing angiogenesis (Roberts et al, 1986;Torre-Amione et al, 1990;Arrick et al, 1992;Glick et al, 1994;Cui et al, 1996). TGF-b conveys signals via two serine/threonine kinase receptors, type I and type II, both of which are necessary for signal transduction Derynck, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

et al. 1998

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The role of Transforming growth factor beta (TGF-b) in carcinogenesis is complex. There are reports on both tumor inhibition and tumor promotion by TGF-b. To elucidate the complex role of TGF-b in epithelial carcinogenesis, we generated transgenic mice overexpressing a dominant negative type II TGF-b receptor in the basal cell compartment and in follicular cells of the skin. Despite the reduced responsiveness of transgenic keratinocytes to TGF-b, both proliferation and di erentiation were normal in non-irritated epidermis of these transgenic mice. Thus, interruption of signaling of all three isoforms of TGF-b in basal and follicular cells does not disturb tissue homeostasis. However, during tumor promotion transgenic mice showed an elevated level of proliferation in the epidermis. This hyperproliferation correlated with a very early onset of carcinoma development and a malignant conversion frequency of 30% from benign papillomas to carcinomas. By comparison, the conversion frequency in wild-type mice of this strain has previously been reported as 5.5%. Even without induction of hyperproliferation by tumor promoters, transgenic mice developed far more carcinomas as controls when treated with a carcinogen. This result indicates that there is a synergistic e ect between loss of TGF-b responsiveness and mutations caused by initiation with a carcinogen leading to an endogeneous tumor promotion in initiated cells only.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

et al. 1998

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“…In cancer cells lacking particular Smad proteins, certain responses to TGF-b thus remain and may positively drive tumor progression. TGF-b may at this late stage of tumor progression function as a tumor promoter in a cell-autonomous manner by promoting tumor cell growth, migration and invasion (Cui et al, 1996;Oft et al, 1998). Furthermore, late stage tumor cells often produce high amounts of TGF-b, which, in a paracrine manner, may stimulate a favorable microenvironment for rapid tumor growth and metastasis by suppressing the immune system and stimulating angiogenesis and extracellular matrix formation .…”

Section: Introductionmentioning

confidence: 99%

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

et al. 2000

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Smads, the intracellular e ectors of transforming growth factor-b (TGF-b) family members, are somatically mutated at high frequency in particular types of human cancers. Certain of these mutations a ect the Smad amino-terminal domain, which, in the case of Smad3 and Smad4, binds DNA. We investigated the functional consequences of four missense mutations in the Smad4 amino-terminal domain found in human tumors. The mutant proteins were found to have impaired abilities to bind DNA although they were fully capable of forming complexes with Smad3. All four Smad4 mutants showed decreased protein stability compared to wild-type Smad4. Two of the Smad4 mutants (G65V and P130S) were translocated to the nucleus and were capable of transactivating a Smad-dependent promoter in a liganddependent manner. In contrast, the L43S and R100T mutants were not translocated e ciently to the nucleus and consequently resulted in severely defective transcriptional responses to TGF-b. Moreover, we demonstrate here the critical importance of two basic residues in the b-hairpin loop of Smad3 or Smad4 for DNA binding, consistent with predictions from the Smad3 crystal structure. In addition, our results reveal that in the TGF-b-induced heteromeric signaling complex, loss of DNA binding of Smad4 can be compensated by Smad3, however, both Smad3 and Smad4 are needed for e cient DNA binding and signaling. In conclusion, mutations in the amino-terminal domain of Smad4, that are found in cancer, show loss of multiple functional properties which may contribute to tumorigenesis. Oncogene (2000) 19, 4396 ± 4404.

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“…Histological studies of bone metastases show that tumour cells remain in the bone marrow cavity and secrete factors that regulate bone cells including parathyroid hormone related protein (PTHrP), tumour necrosis factor (TNF), interleukin-6 (IL-6) and transforming growth factor (TGF)b (Yin et al, 2005). Among these local factors, serum TGFb was recently shown to be associated with disease progression and poor prognosis in patients with metastatic breast cancer (Cui et al, 1996;Sheen-Chen et al 2001;Ivanovic et al, 2003). Matrix-metalloproteases (MMPs) are a family of zincdependent endopeptidases, which degrade the extracellular matrix proteins.…”

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confidence: 99%

Association of 12 serum biochemical markers of angiogenesis, tumour invasion and bone turnover with bone metastases from breast cancer: a crossectional and longitudinal evaluation

Voorzanger-Rousselot¹,

Juillet²,

Mareau³

et al. 2006

Br J Cancer

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Complex biological pathways including angiogenesis, invasion, osteoclastic activation and bone matrix degradation are involved in the formation of bone metastasis (BM). The aim of our study was to investigate the cross-sectional and longitudinal associations of a panel of 12 serum biochemical markers reflecting biological pathways underlying BM development. In a cross-sectional study, we investigated 29 patients with primary breast carcinoma without BM (BC/BMÀ), 28 patients with breast carcinoma and BM (BC/ BM þ ) and 15 healthy women. In longitudinal analyses, we investigated 34 patients for whom serum was obtained a two different time points: at the time of primary BC diagnosis and after a median time of 3 years. During this follow-up, 15 patients developed BM, whereas the other 19 remained free of BM. In patients who developed BM, the second samples were obtained before BM was documented by bone scan. The cross-sectional analyses have shown all biochemical markers to be significantly elevated in patients with BM, when compared to the patients without BM and healthy controls, except TGFb1 that was significantly decreased. Multivariable analyses showed that only the bone resorption markers TRACP 5b, CTX and ICTP, and the marker of angiogenesis VEGF were independently associated with BM. Those markers correctly distinguished 85% of BC patients with or without BM from normal individuals. Longitudinal analyses showed that patients with primary BC who developed BM during follow-up had higher levels of TRACP5b ( þ 95%, P ¼ 0.08) at the time of primary diagnosis, those patients had also a higher increases of ICTP (P ¼ 0.006), MMP-7 (P ¼ 0.004) and TIMP-1 (P ¼ 0.017) during follow-up than patients who did not progress toward bone metastasis. This study provides evidence of increase and interrelationship of circulating markers of angiogenesis, invasion and bone resorption in patients with BC with and without BM. Markers of bone resorption have the highest independent diagnostic value for detecting and potentially predicting BM in breast carcinoma patients. Bone is one of the most common sites of metastasis for certain types of tumours, especially prostate, breast and lung carcinoma (Mundy, 2002). Breast cancer progression to bone is a defining feature of a highly malignant tumour and the major cause of cancer-treatment failure. Early detection of bone metastasis is critical for clinical management and accurate staging of tumours. Currently there is no a simple way to reliably detect and predict which patients will develop bone metastasis. The detection of bone metastases relies on imaging technology, but novel approaches based on biomarker assessments are under intense investigation. Increasing body of data suggests that metastatic dissemination is site specific (Horak and Steeg, 2005) and that distinct molecular factors regulate bone metastasis formation (Yin et al, 2005). A multifactorial and multistep process of bone metastasis formation involves several biological mechanisms including angiogenesis, invasion through...

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TGFβ1 Inhibits the Formation of Benign Skin Tumors, but Enhances Progression to Invasive Spindle Carcinomas in Transgenic Mice

Cited by 586 publications

References 65 publications

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

Association of 12 serum biochemical markers of angiogenesis, tumour invasion and bone turnover with bone metastases from breast cancer: a crossectional and longitudinal evaluation

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