Recruitment of a myeloid cell subset (CD11b/Gr1^mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis*

Abstract

Liver metastasis from colorectal cancer is a leading cause of cancer mortality. Myeloid cells play pivotal roles in the metastatic process, but their prometastatic functions in liver metastasis remain incompletely understood. To investigate their role, we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells. Among the heterogeneous myeloid infiltrate, we identified a distinct population of CD11b/Gr1 mid cells different from other myeloid populations previously associated with liver metastasis. These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2. Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets. Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1 mid recruitment and decreased tumor burden. Depletion of the CD11b/Gr1 mid subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation. There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1 mid cells. Additionally, an analogous myeloid subset was found in liver metastases of some colorectal cancer patients. Conclusion: Collectively, our findings highlight the importance of myeloid cells-in this case a selective CD11b/Gr1 mid subsetin sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy. (HEPATOLOGY 2013;57:829-839) M etastatic colorectal cancer (CRC) is a prominent cause of cancer mortality worldwide. 1 Hepatic metastases are found in approximately 15% of CRC patients at primary diagnosis 2 with 14% subsequently developing metastases.3 Development of new treatment modalities for CRC liver metastasis is urgently required and a greater understanding of the biology of this process will help establish new therapeutics aimed at downstaging the disease, improving operability, and prolonging survival.Metastasis is a multistep process involving complex and continuous interactions between tumor cells and the host microenvironment.4 Several myeloid-derived cell types have been shown to play key roles in the metastatic cascade, including intravasation, extravasation, 5 and colonization at secondary sites by stimulating tumor cell proliferation and angiogenesis and suppressing antitumor immunity.6-8 However, delineation of their roles in metastasis is complicated by the heterogeneity of myeloid phenotypes that appears to be both tumor-and organ-selective. Vascular endothelial growth factor receptor 1 (VEGFR1) þ hematopoietic progenitor cells accumulated at premetastatic sites to promote adherence and growth of lung Lewis carcinoma (LLC) and B16F1 tumor cells, 9 while a Mac-1 þ myeloid population with different markers was

Inflammatory chemokines and metastasis—tracing the accessory

“…Kowanetz and colleagues showed that suggesting that direct interaction of the tumor cell-derived chemokine with monocytes is necessary for efficient tumor cell extravasation (67). In contrast, metastasis of B16-BL6 melanoma cells was independent of CCR2 expression, suggesting that some tumor cells use other means for tumor cell extravasation which remain to be determined (67,68).…”

“…CCL5-expressing tumor cells showed a significant reduction in lung metastasis in S100A4 -/-mice, while liver metastasis was not affected, indicating that at least metastases to the lungs are highly dependent on the interplay between CCL5 and S100A4. Despite these open questions, inhibition of CCL2 or CCR2 was reported to be beneficial in inhibiting metastasis of various cancer types such as breast, bladder, colorectal or prostate cancer in experimental models (66)(67)(68). Based on this preclinical evidence, two clinical trials have been started, evaluating safety and efficacy of blocking both CCL2 and CCR2 in metastatic patients (http://www.clinicaltrials.gov: NCT00992186, NCT01015560).…”

“…The initial trial for the treatment of patients with metastatic castration-resistant prostate cancer used the antibody "CNTO 888" which blocks CCL2. However, blocking CCL2 proved to be less effective possibly due to induced compensatory mechanisms that led to an increase in CCL2 expression (68). In a second ongoing phase II trial, the anti-CCR2 antibody "MLN1202" is being used for treatment of patients with bone metastasis.…”

A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer

“…One major bottleneck of metastatic inefficiency is dictated by the unique tissue microenvironments at secondary sites, called metastatic niches 18 , highlighting the importance of understanding site-specific metastasis. The metastatic niche is unique to the site of recurrence, and is, in part, characterized by deposition of distinct extracellular matrix proteins 19,20 , infiltration of various immune cell populations [21][22][23] , and altered tissue homeostasis including dysregulated production of numerous cytokines, chemokines, and growth factors 15,18,24,25 . Thus, an understanding of the tissue specific metastatic niche precedes an understanding of how to target metastatic disease.…”

Metastatic Growth Progression Caused by PSGL-1–Mediated Recruitment of Monocytes to Metastatic Sites

“…In particular, initiation of metastasis is dependent on the recruitment of leukocytes that is mediated by chemokines (24,25). Tumorderived CCL2 expression drives the recruitment of inflammatory monocytes that facilitates tumor cell extravasation and thereby metastasis (26)(27)(28)(29). Yet, the mechanism of leukocyte adhesion and recruitment to metastatic tumors remains to be identified.…”