Activation of CCR9/CCL25 in Cutaneous Melanoma Mediates Preferential Metastasis to the Small Intestine

Abstract

Purpose: Specific chemokines and their respective receptors have been implicated in distant tumor cell metastasis. Cutaneous melanoma has a distinct pattern of metastasis, preferentially targeting the submucosa of the small intestine. However, the underlying pathogenic mechanism remains unknown. Migration of CCR9(+) lymphocytes to the small intestine is known to occur in response to the chemoattractant effects of CCL25 (thymus-expressed chemokine). The integrin heterodimers ah are also known to be important mediators of cellular adhesion. We hypothesize that the mechanism of small intestinal metastasis by melanoma is via the CCR9-CCL25 axis and specific integrins. Experimental Design: Quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry were used to assess melanoma tumors for CCR9 and CCL25. Integrin expression was assessed using flow cytometry. CCR9 expression by quantitative reverse transcription-PCR was assessed in primary (n = 23) and metastatic (n = 198) melanomas, and melanoma lines derived from small intestinal metastases (n = 23). Results: We showed CCR9 expression in 88 of 102 paraffin-embedded metastatic melanomas from the small intestine, 8 of 8 melanoma lines derived from metastases in the small intestine, and 0 of 96 metastatic melanomas from other sites. In vitro migration and invasion studies done on CCR9(+) melanoma lines showed migration in response to CCL25 that was inhibited by anti-CCR9 antibody or by short interfering RNA CCR9. Flow cytometric analysis confirmed CCR9 expression by melanomas to the small intestine and showed concomitant a 4 h 1 integrin expression. Conclusions: Our findings show that functionally active CCR9 on melanoma cells facilitates metastasis to the small intestine. The CCR9-CCL25 axis may explain the high incidence of melanoma metastasis to this specific location.Human cutaneous melanoma is the most common cancer to metastasize to the small intestine (1, 2), for reasons that remain unclear. However, small intestinal metastases from other solid tumors are rare when compared with their incidence of hepatic and other organ metastases (3, 4). In the largest reported series of melanoma patients with gastrointestinal metastases, lesions were more common in the small intestine than the stomach, colon, or rectum (5). Diagnosis and management of patients with small intestinal metastases is often difficult due to their insidious nature. Most patients initially have nonspecific symptoms; symptoms caused by gastrointestinal hemorrhage or bowel obstruction are highly specific but also represent a surgical emergency. Several prognostic markers have been investigated for patients with clinically localized primary cutaneous melanoma, but none has been linked to organspecific metastasis. A biomarker for the risk of gastrointestinal metastasis would allow a tailored postoperative follow-up program to identify visceral spread of melanoma at an early, nonemergent stage.Metastasis to certain organ sites, such as bone marrow, lung, and liver, are primari...

Signaling Pathways Altered During the Metastatic Progression of Melanoma

“…CXCR4 was identified as the most frequent expressed chemokine receptor in liver metastasis of paraffinembedded tissue, with 89% of the samples expressing it [113]. CCR9 was observed as expressed in a great majority of intestine metastasis of melanoma, but not in other organs [114].…”

Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells

“…The chemokine receptor CCR9 was initially identified for its role in the immune system, where it is present on leukocytes and is critical in T-cell development and responsible for recruiting immune cells to the small intestine [14][15][16]. We now know that CCR9 expression is also associated with poor prognosis and increased cancer cell invasiveness in malignant conditions, including melanoma, ovarian, breast, and prostate cancers [16][17][18].…”

“…We now know that CCR9 expression is also associated with poor prognosis and increased cancer cell invasiveness in malignant conditions, including melanoma, ovarian, breast, and prostate cancers [16][17][18]. CCR9 shows aberrant expression on pancreatic cancer cells [19] and may be a factor in promoting pancreatic cancer progression.…”

Chemokine 25–induced signaling suppresses colon cancer invasion and metastasis

“…Small intestinal epithelial cell CCR9 increases local immune response, while colonic epithelial cell CCR9 reduces inflammation, possibly by acting as a CCL25 "sink" (15). Furthermore, melanoma and ovarian, breast, and prostate adenocarcinomas express CCR9 (21)(22)(23)(24)(25). This is proposed to play a role in tumor cell antiapoptosis and proliferation.…”