Diagnostic dilemmas of squamous differentiation in prostate carcinoma case report and review of the literature

We report a case of pure squamous cell carcinoma involving the prostate and urinary bladder and describe the diagnostic dilemmas that we faced in trying to determine its origin. The patient was diagnosed ten years ago with prostatic adenocarcinoma treated with radioactive seed implantation. During the last year he also underwent a TURP procedure for urinary obstruction complicated by multiple infections. Postsurgery, the patient developed colo-urethral fistula and decision to perform cystprostatectomy was taken. Excision illustrated a tumor mass replacing the entire prostate that microscopically proved to be squamous cell carcinoma. The challenge that we encountered was to determine its origin, the possibilities being divergent differentiation from adenocarcinoma post radiation therapy, de novo neoplasm or urothelial carcinoma with extensive squamous differentiation. Our literature review showed also that the etiology of prostatic squamous carcinoma is still unclear. We present our approach in an attempt to solve this dilemma

Selective inhibition of the human tie-1 promoter with triplex-forming oligonucleotides targeted to ets binding sites

The Tie receptors (Tie-1 and Tie-2/Tek) are essential for angiogenesis and vascular remodeling/integrity. Tie receptors are up-regulated in tumor-associated endothelium, and their inhibition disrupts angiogenesis and can prevent tumor growth as a consequence. To investigate the potential of anti-gene approaches to inhibit tie gene expression for anti-angiogenic therapy, we have examined triple-helical (triplex) DNA formation at 2 tandem Ets transcription factor binding motifs (designated E-1 and E-2) in the human tie-1 promoter. Various tie-1 promoter deletion/mutation luciferase reporter constructs were generated and transfected into endothelial cells to examine the relative activities of E-1 and E-2. The binding of antiparallel and parallel (control) purine motif oligonucleotides (21-22 bp) targeted to E-1 and E-2 was assessed by plasmid DNA fragment binding and electrophoretic mobility shift assays. Triplex-forming oligonucleotides were incubated with tie-1 reporter constructs and transfected into endothelial cells to determine their activity. The Ets binding motifs in the E-1 sequence were essential for human tie-1 promoter activity in endothelial cells, whereas the deletion of E-2 had no effect. Antiparallel purine motif oligonucleotides targeted at E-1 or E-2 selectively formed strong triplex DNA (K(d) approximately 10(-7) M) at 37 degrees C. Transfection of tie-1 reporter constructs with triplex DNA at E-1, but not E-2, specifically inhibited tie-1 promoter activity by up to 75% compared with control oligonucleotides in endothelial cells. As similar multiple Ets binding sites are important for the regulation of several endothelial-restricted genes, this approach may have broad therapeutic potential for cancer and other pathologies involving endothelial proliferation/dysfunction

Overexpression of hepatoma-derived growth factor in melanocytes does not lead to oncogenic transformation

<p>Abstract</p> <p>Background</p> <p>HDGF is a growth factor which is overexpressed in a wide range of tumors. Importantly, expression levels were identified as a prognostic marker in some types of cancer such as melanoma.</p> <p>Methods</p> <p>To investigate the presumed oncogenic/transforming capacity of HDGF, we generated transgenic mice overexpressing HDGF in melanocytes. These mice were bred with mice heterozygous for a defective copy of the Ink4a tumor suppressor gene and were exposed to UV light to increase the risk for tumor development both genetically and physiochemically. Mice were analyzed by immunohistochemistry and Western blotting. Furthermore, primary melanocytes were isolated from different strains created.</p> <p>Results</p> <p>Transgenic animals overexpressed HDGF in hair follicle melanocytes. Interestingly, primary melanocytes isolated from transgenic animals were not able to differentiate <it>in vitro </it>whereas cells isolated from wild type and HDGF-deficient animals were. Although, HDGF^-/-/Ink4a^+/-mice displayed an increased number of epidermoid cysts after exposure to UV light, no melanomas or premelanocytic alterations could be detected in this mouse model.</p> <p>Conclusions</p> <p>The results therefore provide no evidence that HDGF has a transforming capacity in tumor development. Our results in combination with previous findings point to a possible role in cell differentiation and suggest that HDGF promotes tumor progression after secondary upregulation and may represent another protein fitting into the concept of non-oncogene addiction of tumor tissue.</p

Highly variable response to cytotoxic chemotherapy in carcinoma-associated fibroblasts (CAFs) from lung and breast

<p>Abstract</p> <p>Background</p> <p>Carcinoma-associated fibroblasts (CAFs) can promote carcinogenesis and tumor progression. Only limited data on the response of CAFs to chemotherapy and their potential impact on therapy outcome are available. This study was undertaken to analyze the influence of chemotherapy on carcinoma-associated fibroblasts (CAFs) <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>The <it>in vivo </it>response of stromal cells to chemotherapy was investigated in 22 neoadjuvant treated breast tumors on tissue sections before and after chemotherapy. Response to chemotherapy was analyzed <it>in vitro </it>in primary cultures of isolated CAFs from 28 human lung and 9 breast cancer tissues. The response was correlated to <it>Mdm2</it>, <it>ERCC1 </it>and <it>TP53 </it>polymorphisms and <it>TP53 </it>mutation status. Additionally, the cytotoxic effects were evaluated in an <it>ex vivo </it>experiment using cultured tissue slices from 16 lung and 17 breast cancer specimens.</p> <p>Results</p> <p>Nine of 22 tumors showed a therapy-dependent reduction of stromal activity. Pathological response of tumor or stroma cells did not correlate with clinical response. Isolated CAFs showed little sensitivity to paclitaxel. In contrast, sensitivity of CAFs to cisplatinum was highly variable with a GI50 ranging from 2.8 to 29.0 μM which is comparable to the range observed in tumor cell lines. No somatic <it>TP53 </it>mutation was detected in any of the 28 CAFs from lung cancer tissue. In addition, response to cisplatinum was not significantly associated with the genotype of <it>TP53 </it>nor <it>Mdm2 </it>and <it>ERCC1 </it>polymorphisms. However, we observed a non-significant trend towards decreased sensitivity in the presence of <it>TP53 </it>variant genotype. In contrast to the results obtained in isolated cell culture, in tissue slice culture breast cancer CAFs responded to paclitaxel within their microenvironment in the majority of cases (9/14). The opposite was observed in lung cancer tissues: only few CAFs were sensitive to cisplatinum within their microenvironment (2/15) whereas a higher proportion responded to cisplatinum in isolated culture.</p> <p>Conclusion</p> <p>Similar to cancer cells, CAF response to chemotherapy is highly variable. Beside significant individual/intrinsic differences the sensitivity of CAFs seems to depend also on the cancer type as well as the microenvironment.</p

Expression of the inhibitor of DNA-binding (ID)-1 protein as an angiogenic mediator in tumour advancement of uterine cervical cancers

The ID protein, an inhibitor of basic helix-loop-helix (HLH) transcription factors, has been involved in multiple cellular processes. To investigate the association between tumour advancement and ID expressions of uterine cervical cancers, the levels of ID-1, ID-2 and ID-3 mRNAs were determined by real-time reverse transcription-polymerase chain reaction and the histoscore with the localisation of ID-1 was determined by immunohistochemistry and patient survival in 60 patients. ID-1 histoscores and mRNA levels both significantly (P<0.05) increased in uterine cervical cancers according to clinical stage regardless of histopathological type or lymph node metastasis. Furthermore, the 36-month survival rate of the 30 patients with high ID-1 was poor (60%), whereas that of the other 30 patients with low ID-1 was significantly higher (83%). ID-1 histoscores and mRNA levels significantly (P<0.0001) correlated with microvessel counts in uterine cervical cancers. Tumour cells show mostly diffuse to strong cytoplasmic expression of ID-1 and also very faint expression in endothelial cells. Moreover, ID-1 expression not only correlated with microvessel counts but also correlated significantly with histoscore. Therefore, ID-1 might work on tumour advancement through angiogenic activity and is considered to be a candidate for a prognostic indicator in uterine cervical cancers

Prostaglandin production in mouse mammary tumour cells confers invasive growth potential by inducing hepatocyte growth factor in stromal fibroblasts

Interactions between stromal and mammary tumour cells play a crucial role in determining the malignant behaviour of tumour cells. Although MMT mouse mammary tumour cells do not produce hepatocyte growth factor (HGF), addition of conditioned medium (CM) from MMT cells to cultures of human fibroblasts derived from skin and breast tissues stimulated the production of HGF, thereby indicating that MMT cells secrete an inducing factor for HGF. This HGF-inducing factor, purified from MMT-derived CM, proved to be prostaglandin E2 (PGE2). Consistently, treatment of MMT cells with indomethacin, an inhibitor of cyclooxygenase, abolished this HGF-inducing activity in MMT-derived CM, while treatment of MMT cells with HGF stimulated cell growth and cell motility. Likewise, HGF strongly enhanced urokinase-type plasminogen activator activity and invasion of MMT cells through Matrigel: a 15-fold stimulation in the invasion of MMT cells was seen by HGF. Finally, MMT cells in the upper compartment were co-cultivated with fibroblasts in the lower compartment of the Matrigel chamber, HGF levels in the co-culture system exceeded the level in fibroblasts alone and suppression occurred with exposure to indomethacin. Together with increase in the HGF level, the invasion of MMT cells was enhanced by co-cultivation with fibroblasts, whereas the increased invasion of MMT cells was significantly inhibited by an anti-HGF antibody and by indomethacin. These results indicate mutual interactions between MMT cells and fibroblasts: MMT-derived PGE2 plays a role in up-regulating HGF production in fibroblasts, while fibroblast-derived HGF leads to invasive growth in MMT cells. The mutual interactions mediated by HGF and prostaglandins may possibly be a mechanism regulating malignant behaviour of mammary tumour cells, through tumour–stromal interactions. © 1999 Cancer Research Campaig

Under the Skin of a Lion: Unique Evidence of Upper Paleolithic Exploitation and Use of Cave Lion (Panthera spelaea) from the Lower Gallery of La Garma (Spain)

ABSTRACT: Pleistocene skinning and exploitation of carnivore furs have been previously inferred from archaeological evidence. Nevertheless, the evidence of skinning and fur processing tends to be weak and the interpretations are not strongly sustained by the archaeological record. In the present paper, we analyze unique evidence of patterned anthropic modification and skeletal representation of fossil remains of cave lion (Panthera spelaea) from the Lower Gallery of La Garma (Cantabria, Spain). This site is one of the few that provides Pleistocene examples of lion exploitation by humans. Our archaeozoological study suggests that lion-specialized pelt exploitation and use might have been related to ritual activities during the Middle Magdalenian period (ca. 14800 cal BC). Moreover, the specimens also represent the southernmost European and the latest evidence of cave lion exploitation in Iberia. Therefore, the study seeks to provide alternative explanations for lion extinction in Eurasia and argues for a role of hunting as a factor to take into account