Elsevier

Human Pathology

Volume 39, Issue 11, November 2008, Pages 1582-1589
Human Pathology

Original contribution
Expression of Yes-associated protein in common solid tumors

https://doi.org/10.1016/j.humpath.2008.04.012Get rights and content

Summary

The Hippo signaling pathway is a highly conserved potent regulator of cell growth, division, and apoptosis. Yes-associated protein (YAP), the nuclear effector of the Hippo pathway, is a highly conserved component of this pathway in mammalian systems. In humans, amplification of the chromosome region containing the YAP gene (11q22) has been reported in several tumor types. This study was performed to determine if YAP expression was present in 4 common types of malignant tumors that have the highest lifetime risk of causing cancer death among men and women in the United States. The YAP expression intensity and distribution were evaluated in normal tissues and compared to the most frequently occurring malignant tumors in these tissues (colonic adenocarcinoma, lung adenocarcinoma, ovarian serous cystadenocarcinoma, and ductal carcinoma of the breast). For each tissue, the nuclear and cytoplasmic YAP expression intensity was scored as negative, low, or high. We found focal expression of YAP in the progenitor and reparative cellular compartments of normal tissue. In contrast, there was strong and diffuse nuclear and cytoplasmic YAP expression in colonic adenocarcinoma, lung adenocarcinoma, and ovarian serous cystadenocarcinoma. We concluded that the potent Hippo growth regulatory pathway shows markedly different expression patterns in normal tissues of the colon, lung, and ovary compared to the 3 common malignant tumor types we examined in these tissues. Our findings suggest that activation of the Hippo signaling pathway may occur through YAP as part of cell proliferation in normal tissue homeostasis and also might be a frequently activated oncogenic pathway in 3 common malignant tumor types.

Introduction

Cancer presently ranks as the second highest cause of death in the United States [1]. Currently among men and women living in the United States, cancers of the lung, breast, colon, and ovary are among the most common types of malignancies resulting in cancer death [2]. The process of carcinogenesis is complex, and it is believed that multiple mechanisms contribute to the development of malignant tumors with disruption of the balance between cell proliferation and apoptosis being among the major mechanisms [3]. Molecular pathways that have a role in the maintenance of tissue homeostasis are critical to the proper control of cell proliferation and apoptosis.

The Hippo pathway, a vital growth regulator of cell proliferation and apoptosis, was initially identified by mosaic screens in Drosophila melanogaster [4], [5]. Information that is known about the Hippo pathway in Drosophila is likely directly applicable to mammalian systems as it has been shown that mammalian homologues are capable of rescuing Drosophila mutants defective in Hippo signaling [6], [7], [8]. The components of this pathway that are highly conserved in mammals include the following: YAP, Lats1/2, Mob, Mst1/2, Sav, Merlin, Expanded 1/2, and Fat 4 (Fig. 1) [5]. Hippo (Hpo) and Warts (Wts), 2 significant core pathway components, belong to the Sterile 20 (Ste20) and Nuclear Dbf2-related (NDR) serine/threonine protein kinase families, respectively [7], [9], [10], [11], [12], [13]. Salvador (Sav), a third major component of the Hippo pathway, is a scaffold protein with 2 WW domains and is homologous to the human ww45 protein [14], [15]. YAP, one of the highly conserved components in mammals, is considered to be a nuclear effector of the Hippo pathway [5], [16]. It has been noted that loss of critical components of the Hippo pathway can lead to uncontrolled cell growth, which implicates this as a tumor suppressor pathway [14].

Studies from several groups, including our own, have suggested that the main genes involved in the Hippo pathway (Hpo, Sav, and Wts) must function in coordination to properly regulate cell proliferation and apoptosis. Given the growing attention to this novel growth regulatory and tumor suppressor pathway, we wanted to investigate the involvement of YAP, the nuclear effector of the Hippo pathway, for expression in human tumors that have a high lifetime risk of causing cancer death among men and women in the United States. The tumors we selected for the study were adenocarcinoma of the lung, ductal carcinoma of the breast (DCB), ovarian serous cystadenocarcinoma (OSC), and colonic adenocarcinoma. Adenocarcinoma of the lung was included in our study because it has currently replaced squamous cell carcinoma as the most frequently occurring form of lung cancer in both sexes with women being more likely than men to have adenocarcinoma as opposed to other types [17]. DCB was studied because it represents the most common histologic type and accounts for up to 80% of all breast cancers [18]. OSC and colonic adenocarcinoma were also included in the study as serous carcinoma is the most common type of ovarian cancer [19] and colonic adenocarcinoma is the most frequently occurring malignant neoplasm of the colon [20].

Section snippets

Tissue samples

Tissue microarray sections were constructed from paraffin-embedded tissue blocks of different types of malignant tumors and their companion normal tissues. Tissues were obtained from the pathology department at The Johns Hopkins Hospital in Baltimore, MD. The diagnoses were verified by evaluation of the histopathologic and immunohistochemical results. All nontumor and tumor slides were reviewed by 2 reference pathologists.

Tissue microarray design

Core needle biopsies of preexisting paraffin-embedded tissues were

Evaluation of YAP expression in the colon

In the assessment of nuclear and cytoplasmic YAP expression intensity, the biopsy specimens from 16 patients with normal colon tissue and 28 patients with neoplastic colonic adenocarcinoma were analyzed. The YAP expression was assessed using immunohistochemistry methods and scored as detailed in the methods and Table 1. There was YAP expression in the nucleus and cytoplasm of the cells in the basal crypt zones (Fig. 2A, black arrow head), which are areas that correlate with the position of the

Discussion

Balancing cell proliferation and apoptosis is essential to proper tissue growth, development, and function. A disruption in this equilibrium can result in excessive tissue loss with subsequent loss of function as in the case of excessive apoptosis [23], or it can result in tumorigenesis if there is inadequate apoptosis coupled to uncontrolled cell proliferation. The Hippo pathway, which has been uncovered with the aid of Drosophila genetic screens, is a potent regulator of tissue homeostasis by

Acknowledgments

The study was sponsored by a channel scholarship from Department of Pathology, El-Minia University, Egypt (M Gayyed). This was also supported by grant no. DK06187 (R Anders; NDDK, Bethesda, MD). A grant was also received from Maryland Cigarette Restitution Fund GI Cancer SPORE CA62924 (A Klein; Annapolis, MD).

We would like to thank the following individuals for their contributions in the preparation and provision of the tissue microarrays (TMA): Pedram Argani (breast TMA), Ie Ming Shih (ovarian

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