AGE binding to RAGE stimulated mesothelial cell activity, and resulted in the overexpression of VCAM-1, a structure for leukocyte adhesion. The AGE-RAGE interaction resulted in HPMC activation, which may promote local inflammation, and thus is implicated in the peritoneal injury found in long-term PD patients.
Since the work of Judah Folkman in the 1970s demonstrating the importance of vascularization on tumour growth the many roles played by tumour stroma have been demonstrated. Vascular endothelial growth factor/vascular permeability factor appears to be the main in vivo inducer of both stromal blood vessels and other components of the tumour stroma. Its action is probably mediated through its strong and long-lasting effect on microvascular permeability leading to fibrin extravasation and organisation ("tumours are wounds that do not heal"). During tumour invasion, stromal fibroblasts participate in the degradation of the extracellular matrix (ECM) by secreting matrix degrading proteases as well as their downstream-activators. Stroma derived factors such as scatter factor/hepatocyte growth factor as well as interactions between neoplastic cells and the ECM can play a role in both tumour cell migration and proliferation. The ECM may also act as a reservoir for growth factors. A novel transcription factor encoded by the c-ets 1 proto-oncogene is likely to be involved in the transcriptional regulation of both tumour vascularization and invasion. This contribution summarizes recent developments in the tumour stroma field.
The relative distribution pattern of the pan-endocrine marker Chromogranin A (Chr A) and the proliferation-associated Ki-67 antigen was investigated in 20 prospectively sampled prostatectomy specimens. In cryostat sections, the Chr A immunoreactivity showed evidence of endocrine differentiation in all 15 prostatic adenocarcinomas. Nine tumors displayed a weak, 5 a moderate, and 1 adenocarcinoma a strong endocrine differentiation. These findings highlight the importance of endocrine differentiation in prostate malignancy that histologically resembles ordinary adenocarcinomas. The simultaneous demonstration of Ki-67 and Chr A revealed that in normal, hyperplastic, and neoplastic prostate tissue Chr A-positive cells were preferentially situated in proximity to Ki-67-labeled cells. This relative distribution pattern of both markers may indicate that endocrine cells are involved in controlling cell proliferation through a paracrine hormonal mechanism. However, an obvious correlation was not found between the degree of endocrine differentiation and proliferative activity in prostatic adenocarcinomas. Furthermore, a coexpression of Ki-67 and Chr A in the same (tumor) cells was not observed suggesting that the endocrine phenotype is only expressed in the G0 phase of the cell cycle as well as in normal, hyperplastic, and neoplastic conditions.
The first steps of stroma generation are of pivotal importance for carcinogenesis because at this stage are initiated both angiogenesis, the prerequisite for continuous tumour growth, and the proliferation of stromal fibroblasts. These developments contribute to the onset of tumour invasion by secreting several matrix-degrading proteases. Both angiogenesis and the production of proteases are tightly controlled at several levels; of significant importance is transcription. The Ets-1 transcription factor transactivates several genes encoding matrix-degrading proteases and is thought to be involved in both tumour vascularization and invasion. This study therefore investigated, by in situ hybridization and immunohistochemistry, the expression of Ets-1 and of two of its target genes, encoding matrix metalloproteinase (MMP) 1 and MMP 9, in order to demonstrate a topographical in vivo correlation between the expression of these three genes during breast cancer formation. All three genes were first expressed within both endothelial cells and stromal fibroblasts during the onset of stroma generation around intraductal and intralobular in situ carcinomas and they were significantly up-regulated in the stroma of invasive ductal and lobular cancers. The results of this study further support the suggested in vivo role of Ets-1 for both angiogenesis and tumour invasion, via matrix-degrading proteases which are already expressed during the early stages of breast carcinogenesis.
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