IJCEP Copyright © 2007-All rights reserved.
Int J Clin Exp Pathol 1(2):98-104;2008

Review Article
Morphologic and Molecular Events at the Invading Edge of Colorectal Carcinomas

Carlos A. Rubio, MD, PhD

Gastrointestinal and Liver Pathology Research Laboratory, Department of Pathology, Karolinska Institute and University Hospital,
Stockholm, Sweden

Received 28 April 2007; accepted with revision 30 May 2007; available online 1 January 2008

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. (IJCEP704001).

Key Words: Colorectal, adenocarcinomas, growing edge, pore formation, proteolysis

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Address all correspondence to: C. A. Rubio, MD, PhD, Gastrointestinal and Liver Pathology Research Laboratory, Department of
Pathology, Karolinska Institute and University Hospital, 17176 Stockholm, Sweden, Fax: 46-8-51774524,  Email:  
Carlos.Rubio@onkpat.ki.se