Morphologic and molecular events at the invading edge of colorectal carcinomas.
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.
Rubio
Carlos A
CA
Gastrointestinal and Liver Pathology Research Laboratory, Department of Pathology, Karolinska Institute and University Hospital Stockholm, Sweden. Carlos.Rubio@onkpat.ki.se
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