Original contributionThe invasive front in endometrial carcinoma: higher proliferation and associated derailment of cell cycle regulators
Introduction
For a tumor to become malignant, several phenomena are important, of which the following are perhaps the most essential: proliferation outweighing cell death, cellular dedifferentiation, and ability to invade the environment and to metastasize. This ability of cancer cells to invade the surrounding stroma and vessels is linked to patient prognosis because of associations with advanced local invasive tumor growth and distant spread. Tumor invasion is a complex process that involves cell attachment, proteolysis of matrix components, migration of cells through the disrupted matrix, proliferation, and angiogenesis [1].
As to the latter 2 phenomena, aberrations in the regulation of cell cycle control lead to uncontrolled proliferation; and angiogenesis is to a large extent regulated by the hypoxia response. The cell cycle, which is progressively deregulated during carcinogenesis, is controlled by cyclins such as cyclins A, D1, and E; cyclin-dependent kinases (CDKs) such as cdk2 and cdk4; cyclin-dependent kinase inhibitors (CKIs) such as p16, p21, and p27; and tumor suppressor gene products such as p53. Overexpression of cell cycle stimulating factors such as the CDKs and cyclins and downregulation of inhibiting factors such as CKIs are frequently found in tumors, including endometrial carcinoma. It is described that they are correlated with a more malignant subtype, a higher proliferation rate, recurrence, and a worse survival in different tumors [2], [3], [4], [5], [6], [7], [8], [9].
Hypoxia-inducible factor 1α (HIF-1α) is the key regulator of the hypoxia response [10] and has been implicated in carcinogenesis and cancer progression in many different epithelia including the female epithelia of the endometrium [11] and breast [12], [13]. HIF-1α is a transcription factor upregulating many genes [14] that are involved in adaptation to low glucose levels such as the glucose transporter Glut-1, carbonic anhydrase IX (CAIX) that regulates pH [15], and vascular endothelial growth factor (VEGF) that is one of the most potent inducers of angiogenesis [16].
Endometrial cancer is the most common malignant tumor of the female genital tract. Estimated incidence of cancer in the uterine corpus in the United States was 40 880 for 2006 (6% of all cancers), with an estimated probability of developing uterine cancer of 1 in 38 [17]. Endometrial cancer derives from the endometrial epithelial lining of the uterine corpus. During cancer progression, some endometrial cancers grow as polyps; but most invade downward into the myometrium. Conceptually, the deepest parts of the tumors invading the myometrium must be the most active and aggressive ones, showing highest proliferation, invasive behavior, and angiogenesis. Such an “invasive front” has been described in, for example, female breast cancer, where the highest proliferation is known to be in the periphery of the tumor [18], but has not been evaluated yet in endometrial cancer. While analyzing expression of cell cycle–related proteins during endometrial carcinogenesis in a previous study (N. H., unpublished data), we noticed a tendency for some proteins to be preferentially expressed at the invasive front of endometrial carcinomas. The aim of the present study was to perform a comprehensive analysis of the topographical expression of cell cycle regulators and proteins related to the hypoxia response, comparing central tumor parts with the invasive front.
Section snippets
Patients and tissues
Paraffin-embedded specimens from endometrioid endometrial carcinoma (n = 33), mucinous carcinoma (n = 1), and serous endometrial carcinoma (n = 5) with tumor and myometrium on one slide were selected from the archives of the Department of Pathology of the University Medical Center, Utrecht, the Netherlands. These tissues were derived from patients operated on between 1992 and 2004. None of the patients received preoperative radio- or chemotherapy.
Hematoxylin and eosin–stained sections were
Cell cycle proteins
Table 2 gives an overview of the expression of the cell cycle–related proteins in the central parts of the tumor and at the invasive front. For MIB-1 (P < .001), cyclin E (P = .018), cdk2 (.001), and p16 (P = .003), differences between the percentages of positive cells in these areas of the tumor were statistically significantly different (Wilcoxon signed ranks test) (further illustrated in Fig. 1A-D). p53 showed a borderline-significant difference between the invasive front and the center
Discussion
The purpose of this study was to objectively investigate differences in topography of proliferation (MIB-1), aberrant expression of cell cycle regulators and HIF-1α with 3 of its downstream factors, Glut-1, CAIX, and VEGF. This is the first study considering this subject in endometrial carcinoma. The concept of an invasive front has been proposed in other cancers, but differences in definitions and methods in these studies make comparisons difficult [20], [21], [22], [23], [24], [25], [26], [27]
Acknowledgments
We thank D. van Wichen from the Department of Pathology, University Medical Center Utrecht, for his support in creating the figures.
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