Expression of Chemokine Receptor CCR6 as a Molecular Determinant of Adrenal Metastatic Relapse in Patients With Primary Lung Cancer

Christophe M. Raynaud; Olaf Mercier; Philippe Dartevelle; Frédéric Commo; Ken André Olaussen; Vincent de Montpreville; Fabrice André; Laure Sabatier; Jean-Charles Soria

Disclosures

Clin Lung Cancer. 2010;11(3):187-191. 

In This Article

Abstract and Introduction

Abstract

Background: Recent studies suggest that chemokines are involved in organ-specific metastatic relapse. We evaluated the potential implications of chemokine receptors in the development of adrenal metastasis after complete resections of primary non–small-cell lung cancer.
Patients and Methods: We studied a unique cohort of 21 primary lung cancers with matched adrenal metastases for the expression of CX3CR1, CXCR4, CCR6, and CCR7, using immunohistochemistry.
Results: Although CXCR4, CX3CR1, and CCR7 were independently expressed in primary and corresponding metastases, CCR6 was clearly overexpressed in adrenal metastases, compared with corresponding primary tumors. Moreover, CCL20, the ligand of CCR6, was preferentially expressed in adrenal tissues that developed metastases.
Conclusion: We report for the first time (to the best of our knowledge) a potential role for the CCR6 receptor in the organ orientation of the development of metastases in lung cancer. We demonstrated a statistically significant overexpression of CCR6 in adrenal metastases compared with primary lung tumors, indicating that the increased production of CCL20 in adrenal glands might contribute to the selective recruitment of CCR6-expressing cancer cells in lung cancer. This study, in concordance with the data obtained in animal models, suggests that the chemokine receptor family constitutes a biologic support of the "seed and soil" theory.

Introduction

Lung cancer is the leading cause of cancer-related deaths in most developed countries, responsible annually for the death of more than one million people worldwide.[1] About 20% of lung cancer cases are small-cell lung carcinomas, and 80% are non–small-cell lung carcinomas (NSCLCs). Many patients (approximately 55%) with primary lung cancer cannot benefit from surgical resection because their disease is already advanced (locally advanced stage IIIB or metastatic stage IV) at their time of initial diagnosis. The 5-year survival rate of these patients is estimated at < 15%.

Around 50% of patients with NSCLC will develop metastases in the lungs, bone, liver, adrenal glands, or head. The standard of care for patients with metastatic NSCLC is systemic chemotherapy, which also aims at treating possible occult micrometastases already present upon diagnosis. The formation of metastatic colonies is not a random process, and it is thought to start early, during the growth of the primary tumor. The often peculiar organ distribution of metastases according to a given primary cancer was first documented in 1989 by Paget[2] and became the basis of the "seed and soil" theory. Even if this phenomenon is now well documented, the underlying mechanisms remain partially elusive.

Chemokines first emerged as key regulators of leukocyte migration, ensuring the localization of cells to either lymphoid or peripheral tissues, depending on their activation state and the inflammatory status of the tissue.[3] The demonstration that cancer cells often overexpress chemokines and chemokine receptors supported a possible role of chemokines and chemokine receptors in the development of cancer and the mechanisms of metastasis. At the molecular level, the phenomenon is explained by an accumulation of (random) genetic changes that deregulate gene-promoter activities, subsequently leading to an overproduction of specific chemokine-related mRNAs and proteins. Of the many selective advantages that could drive tumor cells to further malignant phenotypes is the autoactivation of cancer growth, because chemokines may act as direct autocrine growth factors in cancer cells. This autocrine function of particular chemokines implies that tumor cells carry chemokine receptors at the cell surface that transduce a mitogenic signal. In this way, interleukin-8 was found to be mitogenic in Kaposi sarcoma cells,[4] ovarian cancer,[5] colon carcinoma,[6] and malignant mesothelioma.[7] Chemokines may also provide paracrine growth advantages via angiogenesis.[8] Finally, chemokines could enhance invasion.[9] The latter point is particularly interesting, because tumor invasion is a process of cell movement through basement membrane barriers and the dense network of extracellular matrix molecules.

One major role proposed for chemokines and mostly chemokine receptor expression involves determining the location of metastases. The direction of leukocyte migration is toward increasing chemokine concentrations.[10] Thus cancer cells may use the same mechanism for tissue and metastatic invasion. Indeed, recent data suggest that chemokine receptors in cancer cells play a key regulatory role in directing lymphatic and hematogenous spread, influencing the sites of metastatic growth of different tumors.[11] In a variety of solid tumors, CXCR4 and CCR7 appear to predict dissemination in the lymph nodes[12–16] or other distant sites.[17–19] Moreover, the overexpression of chemokine receptors such as CCR6 and CX3CR1 may contribute to the process of cancer cells "homing" to specific organs.[20]

Here, we evaluated the expression of CXCR4, CX3CR1, CCR6, and CCR7 in a series of 21 patients treated at the same hospital who had undergone surgery of both their primary lung tumor and its related metachronous or synchronous adrenal gland metastasis. We tested the hypothesis that the expression of these chemokine receptors could lead to the adrenal homing of a metastasis.

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