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Denmark↗
Biomedical subjects
Paul van Diest
Publications and source records attributed to Paul van Diest.
Amplifications of the epidermal growth factor receptor gene (egfr) are common in phyllodes tumors of the breast and are associated with tumor progression.
Phyllodes tumors of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. An important role of the epidermal growth factor receptor (EGFR) in phyllodes tumors has been proposed. However, detailed pathogenetic mechanisms remained unclear. We investigated 58 phyllodes tumors of the breast (40 benign, 10 borderline and eight malignant) by means of egfr fluorescence in situ hybridization (FISH) and gene dosage PCR for a regulatory sequence within intron 1 of egfr. Immunohistochemical staining was performed for EGFR, p16, p21, p27, p53, c-myc, Cyclin A, Cyclin D1, Cyclin E, c-kit and Ki67. Immunopositivity for EGFR was detected in 19% of phyllodes tumors (75% of all malignant tumors) in stromal tumor cells but not in the epithelial component. Whole-gene amplifications were seen by FISH in 15.8% (in stromal cells only) and intron 1 amplifications by gene dosage PCR in as much as 41.8% of all phyllodes tumors. Significant correlations were seen between tumor grade on the one hand and EGFR overexpression (P=0.001) and intron 1 amplifications (P<0.05) on the other. EGFR overexpression further correlated positively with immunohistochemical staining for p53, p16, Cyclin A, Cyclin E, Ki67 and c-kit. Presence of intron 1 amplifications correlated with p16 (P<0.01), p21 (P=0.009) and p53 immunoreactivity (P<0.001). Neither EGFR overexpression nor whole-gene amplification was observed in a control series of 167 fibroadenomas and only one of 43 (2.3%) exhibited intron 1 amplification in gene dosage PCR. In conclusion, our results show for the first time that activating mutations in and overexpression of egfr are associated with the progression in grade of phyllodes tumors of the breast. The observed association between intron 1 amplification and overexpression of EGFR provides further insight into regulation mechanisms of EGFR overexpression.
Base Sequence↗
Dual effect of Kras(D12) knockdown on tumorigenesis: increased immune-mediated tumor clearance and abrogation of tumor malignancy.
Activating mutations in the human KRAS proto-oncogene are acquired during the earliest stages of colorectal cancer development. If mutant KRAS is to be used as a target for therapy in colorectal cancer, tumor growth should depend on its continued presence. Here, we report that stable knockdown of Kras(D12) in murine C26 colorectal cancer cells by RNA interference resulted in loss of transformed properties in vitro. The incidence of subcutaneous tumor formation was reduced by 60% and the lag time was increased sevenfold. Kras(D12)-knockdown tumors grew noninvasively and did not cause morbidity. Remarkably, some of the Kras(D12)-knockdown tumors regressed spontaneously, which rendered these mice resistant to parental C26 tumor growth. In immune-deficient hosts, the incidence of tumor formation by Kras(D12)-knockdown cells was 100%. None of these tumors regressed spontaneously. We conclude that the reduced incidence of tumor formation by Kras(D12)-knockdown cells is due to tumor cell clearance by the host immune system, but not to an intrinsic inability of these cells to grow out as tumors. Interestingly, Kras(D12) knockdown resulted in increased production of interleukin 18 (Il-18), an immune-stimulatory cytokine that has been implicated in limiting colorectal tumor formation. Thus, mutant Kras(D12) suppresses Il-18 production in colorectal tumor cells, which may contribute to evasion of the local immune system during tumor development.
Animals↗
Centromeric chromosomal translocations show tissue-specific differences between squamous cell carcinomas and adenocarcinomas.
Structural chromosomal aberrations are common in epithelial tumors. Here, we compared the location of centromeric breaks associated with whole arm translocations in seven adenocarcinoma cell lines and nine squamous cell carcinoma cell lines using SKY, microarray-based comparative genomic hybridization (array CGH) and fluorescence in situ hybridization (FISH). Whole arm translocations were more frequent in squamous cell carcinomas (112 in nine cell lines and nine in one short-term culture) than in adenocarcinomas (13 in seven cases) and most often resulted in copy number alterations. Array CGH analysis demonstrated that in all squamous cell carcinomas and in most adenocarcinomas, the breakpoints of unbalanced whole arm translocations occurred between the two clones on the array flanking the centromeres. However, FISH with centromeric probes revealed that in squamous cell carcinomas, the marker chromosomes with whole arm translocations contained centromeres comprised of material from both participating chromosomes, while in adenocarcinomas centromeric material from only one of the chromosomes was present. These observations suggest that different mechanisms of centromeric instability underlie the formation of chromosomal aberrations in adenocarcinomas and squamous cell carcinomas.
Adenocarcinoma↗
Cyclooxygenase-2 is a target of KRASD12, which facilitates the outgrowth of murine C26 colorectal liver metastases.
PURPOSE: Mutational activation of the KRAS oncogene and overexpression of cyclooxygenase-2 (COX-2) contribute to colorectal carcinoma (CRC) development, but the relationship between these two events is unclear. This study was designed to clarify that relationship and to assess the contribution of KRAS-dependent COX-2 to the seeding of CRC cells in the liver and to their outgrowth as liver metastases in an experimental mouse model. EXPERIMENTAL DESIGN: The effect of RNA interference-mediated KRAS knockdown on COX-2 expression and activity was tested in murine C26 CRC cells. The contribution of KRAS-dependent COX-2 to early metastatic tumor cell seeding (by intravital microscopy) and outgrowth of metastases in the liver (by bioluminescence imaging) was studied by using parecoxib, a novel and highly selective liver-activated COX-2 inhibitor. Intratumoral cell proliferation, apoptosis, and tumor-associated angiogenesis were assessed by immunohistochemistry on liver tissue sections. RESULTS: Stable knockdown of mutant KRAS(D12) in murine C26 CRC cells by RNA interference lead to a dramatic reduction of COX-2 synthesis and prostaglandin E2 production. Inhibition of host or tumor cell COX-2 activity had no effect on early metastatic cell seeding in the liver but greatly reduced intrahepatic tumor cell proliferation and the rate of liver metastasis outgrowth. COX-2 inhibition had no effect on early tumor vascularization or on tumor cell apoptosis. CONCLUSIONS: The high levels of COX-2 enzyme and prostaglandin production in C26 CRC cells are primarily caused by the presence of endogenous mutant KRAS(D12). Furthermore, COX-2 inhibition affects the tumoral rather than the vascular compartment during the early stages of C26 liver metastasis outgrowth.
Animals↗
Chromosomal changes in relation to clinical outcome in larynx and pharynx squamous cell carcinoma.
Invasive head and neck squamous carcinomas are among the cytogenetically most complex tumors. Perhaps for this reason, there is little consensus on the prognostic value of specific chromosomal aberrations. Here we present results of CGH analysis of 56 clinically well-characterized set of head and neck cancers, consisting of larynx and pharynx only. The aim was to find possible associations with clinical outcome. The major chromosome arms showing gains were (in decreasing order): 3q, 7q, 8q, 5p, 11q13, 17q and 18p, and losses occurred at 3p, 11qter, 4p, 18q, and 5q. The segments most frequently amplified were 3q26-qter, 11q13, 11q22, 3q12-13, 18p11.3, 18q11.2 and 8q24.3. Tumors with stages III and IV, and lymph node positive tumors had a worse clinical outcome. Surprisingly, no specific chromosomal abnormality correlated with disease-free survival. The only aberration that correlated to one of the clinico-pathological parameters was amplification 11q13, that occurred solely in lymph node positive, stage IV tumors. However 11q13 amplification did not correlate with disease-free survival. These results seem to indicate that genetic alterations at the level of chromosomes have limited prognostic value in patients with invasive larynx and pharynx squamous cell carcinomas.
Adult↗
Growing mass in the right suprascapular region.
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Female↗
Molecular signature associated with bone marrow micrometastasis in human breast cancer.
Metastasis is the leading cause of cancer-related death, and bone marrow (BM) is a prominent metastatic site in solid tumors. Here, we focused on the onset of metastasis, using BM as an indicator organ for micrometastatic tumor cells in breast cancer patients without overt metastases (tumor-node-metastasis stage M(0)). Expression analysis with cDNA arrays showed distinct profiles between primary tumors from BM-positive and BM-negative patients. The differentially expressed genes are involved in extracellular matrix remodeling, adhesion, cytoskeleton plasticity, and signal transduction (in particular RAS and hypoxia-inducible factor 1alpha pathway). The BM signature was mainly characterized by transcriptional repression and different from the expression signature associated with lymphatic metastasis. Thus, BM micrometastasis is a selective process with a specific molecular signature of the primary tumor.
Bone Marrow Neoplasms↗