This study demonstrates that multiple chemokine receptors are expressed in significant proportions in primary and adrenal metastases. To our knowledge, this is the first report to investigate molecular events that might explain the adrenal-specific metastatic development of primary lung tumors. Here, CCR6 was significantly overexpressed at sites of adrenal metastasis compared with corresponding primary lung tumors. This might reflect the selection of a subpopulation of cells expressing CCR6 in the process of adrenal gland homing. This assumption is further reinforced by the finding that normal adrenal tissue surrounding tumor cells commonly overexpresses the CCR6 ligand CCL20. However, it is questionable whether or not the metastatic migration of tumor cells is governed over long distances by the chemotactic gradient of a single chemokine. Metastasis is a complex phenomenon that involves the ability of tumor cells both to migrate to a particular site and to establish themselves and proliferate. Thus, the prevailing view of chemokines as mere attractants for tumor cells may be oversimplified.[11,21]
Reportedly, CCR7 was implicated in the specific distant-site homing of cancer cells in NSCLC. Takanami reported that CCR7 overexpression in NSCLC correlated with lymph node metastasis. Because no differences were evident in our study between primary and corresponding metastases, no role for CCR7 may exist in the development of specific adrenal metastases. However, we demonstrated a strong expression pattern of CCR7 in a majority of both primary and metastatic cells. Cancer cells may use the receptor CCR7, as do dendritic cells, to facilitate their entry into lymphatic vessels and their subsequent retention within CCL21-rich, secondary lymphoid organs.[16,22–24] In addition, lymphatic vessel invasion is the first step required for a majority of lung cancers in establishing distant metastases. Therefore, the observation of high CCR7 expression in tumors from patients with metastatic disease is not surprising.
Moreover, CXCR4 and CXCR1 were previously studied as possible molecular determinants of the homing of tumor metastases.[12–19] In our study, we found too few cases with a positive expression of CXCR4, making it difficult to draw a clear conclusion. We were also unable to confirm CCR7 as predictive of the lymph node dissemination of tumor cells, which probably reflects the importance of organ-specific or tissue-specific mechanisms for metastatic homing. Indeed, the recognition of CCR6 and CCL20 seems to be important in adrenal metastatic processes but is of no relevance in other organs, where other chemokines may be more strongly implicated. For instance, other cancers, such as breast cancer, were reported to metastasize preferentially to the liver, brain, skin, and pleura according to the expression levels of, respectively, CXCR4, CX3CR1, CCR7, and CCR6 in the primary tumor.
Various in vitro and animal studies provide evidence that chemokines selectively expressed in certain tissues can promote metastasis by attracting specific CCR-expressing tumor cells or by providing growth-stimulatory signals. Based on this concept, increased levels of CCR6 expression in adrenal metastatic cells could reflect the chemoattraction of lung cells by CCL20 expressed in the adrenal glands. The identification of key targets promoting metastasis is of great interest for the development of specific treatment strategies. Attempts to inhibit metastasis by interfering with chemokine receptor/chemokine interactions may lead to a promising new treatment strategy. Various small-molecule chemokine receptor antagonist compounds are undergoing development in phase I-III studies in infectious and autoimmune diseases, and more recently, in cancer. The targeting of CCR6 and CCL20 might represent a treatment strategy that could be developed for the prevention of adrenal recurrences.
Clin Lung Cancer. 2010;11(3):187-191. © 2010 CIG Media Group, LP
Cite this: Expression of Chemokine Receptor CCR6 as a Molecular Determinant of Adrenal Metastatic Relapse in Patients With Primary Lung Cancer - Medscape - May 01, 2010.