Resistance to TGF-b1 occurred in pancreatic cancer cells suggesting that inactivation of TGF-b inhibitory signaling pathways may play an important role in human pancreatic cancer. The aim of our study was to determine the presence of alterations in the main putative components of the TGF-b inhibitory signaling pathways (p15, Smad4, Smad2, TGFb-RII, CDC25A). A panel of human carcinomas of the exocrine pancreas orthotopically implanted and perpetuated in nude mice and pancreatic cancer cell lines were studied. p15 gene alterations, mainly homozygous deletions that involved exons 1 and/or 2, were found in the 62.5% (5 of 8) of pancreatic xenografts whereas Smad4 gene aberrations were found in one of eight xenografts and in two of seven cell lines. Additional aberrations in these genes were acquired during in vivo perpetuation and distal dissemination. Paradoxically, TGFb-RII overexpression and a decrease in CDC25A protein levels were found in all tumors and cell lines. In one cell line, resistance to TGFb1 occurred in the absence of alterations in the genes analysed so far. We conclude that all human pancreatic tumor cells analysed herein have non-functional TGF-b pathways. The majority of cells harbor alterations in at least one of the putative components of TGF-b pathways, mainly in p15 and Smad4 genes. These results suggest that inactivation of TGF-b signaling pathways plays an important role in human pancreatic tumorigenesis.

Given the number of centers involved and the size of the database, we feel that our results broadly reflect current practice in the use of HFOV in pediatric patients. These results may help in deciding which patients are most likely to benefit from aggressive intervention by using extracorporeal techniques and may help identify high-risk populations appropriate for prospective study of innovative modes of supporting gas exchange (e.g., partial liquid breathing or intratracheal pulmonary ventilation).

Integrin alphavbeta3 (vitronectin receptor) has been implicated in human malignant melanoma progression and angiogenesis as a receptor that provides survival signals. However, little is known about the therapeutic potential of antagonists of alphavbeta3. In this report, we characterize the activities of 2 antagonists of alphavbeta3 integrins: a human specific monoclonal antibody (MAb), 17E6, and a cyclic RGD peptide that blocked cell adhesion and induced detachment of previously substrate-attached cells in vitro. In vivo, alphavbeta3 antagonists behaved as anti-tumor drugs in a dose- and time-dependent manner. Moreover, different therapeutic treatments proved to be effective even in the therapy of established macroscopic tumor masses, thus supporting the use of these antagonists in clinical therapy. Using a panel of 6 human melanomas and 5 carcinomas, MAb 17E6 efficiently blocked the in vivo tumor growth of melanomas expressing alphavbeta3 as xenografts but did not affect the alphavbeta3-negative (although alphav integrin-positive) tumors. This demonstrated that alphavbeta3 is a pivotal integrin for the growth of human melanomas. Furthermore, since MAb 17E6 does not recognize murine alphavbeta3, the effect is due only to the direct anti-tumor activity and not to the well-known anti-angiogenic activity of alphav-integrin antagonists. Taken together, our results confirm the essential role of alphavbeta3 integrin in the growth of human malignant melanoma in vivo and provide strong evidence of the therapeutic potential of alphav-integrin antagonists for the treatment of such tumors.

p53 mutations alone or in combination with K-ras mutations are correlated with a worse outcome. However, the routine use of these mutations as prognostic markers in the clinical setting is not recommended.

Integrin αvβ3 (vitronectin receptor) has been implicated in human malignant melanoma progression and angiogenesis as a receptor that provides survival signals. However, little is known about the therapeutic potential of antagonists of αvβ3. In this report, we characterize the activities of 2 antagonists of αvβ3 integrins: a human specific monoclonal antibody (MAb), 17E6, and a cyclic RGD peptide that blocked cell adhesion and induced detachment of previously substrate‐attached cells in vitro. In vivo, αvβ3 antagonists behaved as anti‐tumor drugs in a dose‐ and time‐dependent manner. Moreover, different therapeutic treatments proved to be effective even in the therapy of established macroscopic tumor masses, thus supporting the use of these antagonists in clinical therapy. Using a panel of 6 human melanomas and 5 carcinomas, MAb 17E6 efficiently blocked the in vivo tumor growth of melanomas expressing αvβ3 as xenografts but did not affect the αvβ3‐negative (although αv integrin‐positive) tumors. This demonstrated that αvβ3 is a pivotal integrin for the growth of human melanomas. Furthermore, since MAb 17E6 does not recognize murine αvβ3, the effect is due only to the direct anti‐tumor activity and not to the well‐known anti‐angiogenic activity of αv‐integrin antagonists. Taken together, our results confirm the essential role of αvβ3 integrin in the growth of human malignant melanoma in vivo and provide strong evidence of the therapeutic potential of αv‐integrin antagonists for the treatment of such tumors. Int. J. Cancer 87:716–723, 2000. © 2000 Wiley‐Liss, Inc.

Chromosome 18q is lost a high proportion of colorectal and pancreatic cancers. Three candidate tumor suppressor genes, DCC, Smad4 and Smad2 have been identi®ed in this chromosome region. DCC and Smad4 aberrations have been previously identi®ed in pancreatic and colorectal tumors. The aim of this study was to compare the presence of concurrent genetic aberrations in DCC and neighboring Smad4 and Smad2 genes during colorectal and pancreatic distal dissemination. We have used a panel of orthotopically implanted colorectal and pancreatic xenografts and corresponding metastases. We have shown that while LOH at DCC locus occurred at a similar frequency in both tumors, diminished DCC protein expression was exclusively present in colorectal tumors harboring intragenic DCC LOH. In contrast, in pancreatic xenografts loss of DCC protein and mRNA expression was restricted to metastases. Smad4 gene aberrations were detected at a similar frequency in both tumors and were selected for during distal dissemination. Acquisition of alterations in both genes occurred independently. Our results suggest that both DCC and Smad4 contribute to pancreatic and colorectal distal dissemination. However, the role of DCC may dier between both tumor types. Oncogene (2000) 19, 546 ± 555.

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Orthotopic transplantation of solid tumor fragments of human tumors in nude mice reproduces their pattern of local growth and distal dissemination. While lymphatic, hepatic or peritoneal dissemination can be reproduced, perineural invasion is absent. Early passages (less than 3) of xenografts show a high degree of stability regarding K-ras, p53 and p16 gene status. On the other hand, advanced passages of tumors acquire additional alterations in the p15 and Smad4 genes. Mutations in K-ras, p53, p15 and Smad4 genes can be acquired, in this model system, in the more advanced stages of pancreatic tumor dissemination. Finally, it is also possible to standardize local growth of these tumors as well as its dissemination pattern giving us a preclinical tool to evaluate the anticancer activity of new drugs.