The clinical potential of chemokine receptor antagonists

Ribeiro, Sofia; Horuk, Richard

doi:10.1016/j.pharmthera.2005.01.004

Cited by 110 publications

(76 citation statements)

References 89 publications

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“…Because Ccr1 −/− mice are healthy unless challenged with specific pathogens (33), therapeutic inactivation of CCR1 may exhibit few side effects. Consistently, several CCR1 antagonists were well tolerated in phase II trials for rheumatoid arthritis and multiple sclerosis (34). It is therefore possible that administration of CCR1 antagonists as an adjuvant therapy after surgical resection of the primary tumors can improve the survival of patients with colorectal cancer that expresses CCL15.…”

Section: Discussionmentioning

confidence: 86%

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Kitamura

Fujishita

Loetscher

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

139

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Recent reports have suggested critical roles of myeloid cells in tumor invasion and metastasis, although these findings have not led to therapeutics. Using a mouse model for liver dissemination, we show that mouse and human colon cancer cells secrete CCchemokine ligands CCL9 and CCL15, respectively, and recruit CD34 + Gr-1 − immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinases MMP2 and MMP9. Lack of the Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Importantly, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization and significantly prolongs the survival of tumor-bearing mice. These results suggest that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver.C olon cancer is one of the leading causes of cancer-related deaths (1). Although most primary tumors can be resected surgically, colorectal cancer frequently spreads to the liver, which is responsible for the high mortality of the disease (2). For successful metastasis, cancer cells need to invade surrounding tissues, penetrate microvessels, survive in circulation, disseminate to distant organs, form micrometastases, and expand into macrometastases. To progress through these steps, tumor cells often acquire the capability of survival and invasion by activating metastatic signaling pathways or inactivating metastasis suppressor genes (2, 3). In addition to these cell autonomous changes, tumor stromal cells, especially bone marrow-derived myeloid cells, actively participate in early steps of the metastatic cascade in some mouse models (4). For example, tumor-associated macrophages (TAMs) promote migration and intravasation of mammary tumor cells (5, 6). Bone marrow-derived cells that express myeloid cell marker CD11b and granulocyte marker Gr-1 (CD11b + Gr-1 + ) also promote metastasis of breast cancer cells, likely through promotion of intravasation and suppression of immune responses (7). Furthermore, CD11b + myeloid cells that express vascular endothelial growth factor receptor 1 (VEGFR1) accumulate at the metastatic sites before the arrival of lung cancer and melanoma cells and foster the dissemination of the cancer cells (8). These reports suggest that bone marrow-derived myeloid cells can help cancer epithelium in early steps of metastasis. It remains to be determined whether therapeutics targeting such myeloid cells can prevent cancer metastasis (9).As a model for invasive colon cancer, we previously constructed cis-Apc +/Δ716 Smad4 +/− (Apc/Smad4) mice that develop intestinal adenocarcinomas with marked invasions by loss of Apc and Smad4 tumor suppressor genes in the intestinal epithelium (10, 11). In the Apc/Smad4 tumors, we reported that the invading cancer epithelium is associated with immature myeloid cells (iMCs) that express myeloid progenitor cell marker CD34 and CD11b (12). Because these iMCs do not express Gr-1 or VEGFR1, they belong to a different subc...

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Section: Discussionmentioning

confidence: 86%

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Kitamura

Fujishita

Loetscher

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

139

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“…CCR5 is a chemokine receptor that plays a critical role in Th1 type immunity to pathogens (19) and is a coreceptor for HIV infection (20). Aberrant up-regulation of CCR5 in T lymphocytes is implicated in the induction of Th1-type responses in rheumatoid arthritis and transplant rejection (21). Therefore, selective attenuation of CCR5 expression in activated lymphocytes might be a novel approach to treat autoimmune disease or HIV infection.…”

Section: Resultsmentioning

confidence: 99%

Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

Peer

Zhu

Carman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

260

201

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“…In agreement with CCR5 deficiency modulating the hepatic inflammatory response, the CCR5⌬32 mutation was recently reported to exacerbate the severity of hepatic inflammation and injury in some T cell-mediated liver diseases (discussed below). In addition, CCR5 has also been implicated in the pathology of numerous autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes (19).…”

Section: Ccr5 Chemokine Receptormentioning

confidence: 99%

CCR5 in T Cell-Mediated Liver Diseases: What’s Going On?

Ajuebor

Carey

Swain

2006

The Journal of Immunology

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The chemokine receptor CCR5 came into worldwide prominence a decade ago when it was identified as one of the major coreceptors for HIV infectivity. However, subsequent studies suggested an important modulatory role for CCR5 in the inflammatory response. Specifically, CCR5 has been reported to directly regulate T cell function in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. Moreover, T cell-mediated immune responses are proposed to be critical in the pathogenesis of autoimmune and viral liver diseases, and recent clinical and experimental studies have also implicated CCR5 in the pathogenesis of autoimmune and viral liver diseases. Therefore, in this brief review, we highlight the evidence that supports an important role of CCR5 in the pathophysiology of T cell-mediated liver diseases with specific emphasis on autoimmune and viral liver diseases.

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The clinical potential of chemokine receptor antagonists

Cited by 110 publications

References 89 publications

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

CCR5 in T Cell-Mediated Liver Diseases: What’s Going On?

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