Morphologic and molecular events at the invading edge of colorectal carcinomas

Abstract

The mechanisms whereby colorectal carcinomas invade the extracellular matrix remain elusive. In a series of studies on the growing edge of colorectal carcinomas, we found dilated neoplastic glands, some with a layer of flat tumor cells, and some lacking one or more groups of consecutive lining tumor cells (called glandular pores). Through the glandular pores, the retained glandular material was siphoned off directly into the juxtaposed extracellular matrix. The substances secreted by the tumor cells, rich in proteolytic enzymes, disrupted the anatomy of the extracellular matrix. To remodel the defective glands, the malignant cells, proliferating from the tip of the free borders of the pores, invade the enzymatically disrupted matrix to achieve glandular continuity. Sealing of these glandular flaws permits intraglandular accumulation of new proteolytic material, a mechanism that replicates a new wave of host invasion at the invading edge, thus ensuring stepwise but everlasting tumor progression in untreated patients. More recent findings indicated that the flat tumor cells at the advancing edge failed to express the proliferation marker Ki67 but overexpressed the mutated p53 protein. This paradoxic biologic behavior of tumor cells may be connected with the subsequent formation of glandular pores and strongly suggests that the arrested cell proliferation at the advancing tumor edge occurs independently of p53 mutation. Possibly, two independent molecular systems exist at the advancing edge of colonic carcinomas, one supervising cell proliferation and the other actively transferring the mutated p53 protein to daughter cells.

Keywords: Colorectal; adenocarcinomas; growing edge; pore formation; proteolysis.

Figure 1

A. Neoplastic gland at the tumor edge. Note the thin layer of tumor cells facing the juxtaposed tissues of the host (colonic adenocarcinoma; H&E, 100×). B. Neoplastic gland at the tumor edge lacking a group of consecutive tumor cells, called glandular pore formation. Note the release of mucin directly into the juxtaposed extracellular matrix of the host (colonic adenocarcinoma; H&E, 200×). C. Overview of the invading tumor showing neoplastic glands with pore formation (colonic adenocarcinoma; MNF 116 immunization, 25×). D. Neoplastic gland at the invading edge of the tumor with intraglandular mucin being released through the pore into the extracellular matrix (rectal adenocarcinoma; H&E, 100×).

Figure 2

A. Neoplastic glands with intraglandular mucin. Note the pore formation, putting the mucin produced by the tumor cells in direct contact with the extracellular matrix (rectal adenocarcinoma; MNF 116 immunostain, 100×). B. Neoplastic gland with pore formation at the invading edge showing overexpression of laminin 5-2, particularly in the neoplastic cells surrounding the pore (colonic adenocarcinoma; laminin 5-2 immunostain, 200×). C. Colonic adenocarcinoma with a dilated neoplastic gland at the invading tumor edge. Note the absence of Ki67 expression in the flat tumor cells (clone MIB 1 immunostain, 200×). D. The same gland as in panel C showing p53 expression in all cells, including the flat tumor cells at the invading tumor edge (immunostain for P53, 200×).