Possible Mechanism Connected with the Progression of Submucosal Invasion in Colorectal Neoplasias

Previous studies in human and in experimentally- induced colorectal carcinomas showed that the material retained in dilated glands at the growing tumour edge was directly released into the peritumoral extracellular matrix (ECM) through glandular faults called glandular pores. In this work, the characteristics of the glands at the growing edge in adenomas with submucosal invasion were investigated in 56 patients. Sections (stained with hematoxylin-eosin, and MNF 116) from 56 colonic adenomas with submucosal invasion were reviewed. Pore formation was defined as a glandular defect characterised by lack of a group of epithelial cells in the deeper portion of the glands. Numerous dilated submucosal glands with pores were found in 46 (82%) of the 56 neoplasias. Through those pores retained mucin, neutophils and/or necrotic material, containing proteolytic enzymes, were siphoned off into the surrounding tissues, causing disruption of the paratumoral ECM and facilitating host penetration by neoplastic cells. Glandular continuity seems to be restored by the proliferation of malignant cells from the tip of the free borders of the pores into the disrupted ECM. The sealing of the glandular flaws would permit the re-accumulation of intra- glandular proteolytic material, a mechanism that would replicate a new wave of host invasion, thus ensuring a stepwise, but continual, tumour progression at the growing edge in untreated patients. In order to study some of the determinants for the acquisition of an invasive phenotype, several parameters pertinent to neoplastic cells have been investigated, e.g. histological configuration and immunohistochemical expression (7), cellular proliferation (26), p53 expression (26), K-ras mutations (26), cyclin E and CDK (10), bcl (26), K(+) ion channels from the HERG1 protein family (9) and carbonic anhydrase-related protein VIII (CA-RP VIII) (14). On the other hand, in order to assess the role played by the extracellular matrix (ECM) in tumour penetration, other parameters have been explored, e.g. angiogenesis (28), telomerase activation (6), cathepsin B (4), CD10 expression (15), increased membrane type 1 matrix metalloproteinase (12), TGF-‚ signalling in fibroblasts (2) and trimeric laminin 5 expression (11). Notwithstanding, despite the burgeoning literature, the mechanism whereby the neoplastic glands invade the juxtaposed normal matrix of the host remains poorly understood.