Lymph node-independent liver metastasis in a model of metastatic colorectal cancer

Abstract

Deciphering metastatic routes is critically important as metastasis is a primary cause of cancer mortality. In colorectal cancer (CRC), it is unknown whether liver metastases derive from cancer cells that first colonize intestinal lymph nodes, or whether such metastases can form without prior lymph node involvement. A lack of relevant metastatic CRC models has precluded investigations into metastatic routes. Here we describe a metastatic CRC mouse model and show that liver metastases can manifest without a lymph node metastatic intermediary. Colorectal tumours transplanted onto the colonic mucosa invade and metastasize to specific target organs including the intestinal lymph nodes, liver and lungs. Importantly, this metastatic pattern differs from that observed following caecum implantation, which invariably involves peritoneal carcinomatosis. Anti-angiogenesis inhibits liver metastasis, yet anti-lymphangiogenesis does not impact liver metastasis despite abrogating lymph node metastasis. Our data demonstrate direct hematogenous spread as a dissemination route that contributes to CRC liver malignancy.

Microsatellite Alterations With Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis

“…These results suggest that there may be a genetic or epigenetic change other than 9p24.2 LOH that is associated with E/L and may promote metastasis to the liver. A recent study by Enquist et al suggested that metastasis to the liver from primary CRC is mediated through hematogenous but not lymphangiogenous spread (35). Therefore, it could be that the presence or absence of 9p24.2 LOH in the E/L background in stage III CRC may also determines the route of dissemination.…”

Lymphangiogenesis and metastasis—A closer look at the neuropilin/semaphorin3 axis

“…Lymphatic invasion was found to correlate more strongly with LN metastasis in human melanoma specimens than vascular invasion (Doeden et al, 2009). Enlarged peritumoral lymphatic vessels are often seen to contain a “plug” of tumor cells inside the vessel (Figure 4A) (Banyard et al, 2014; Enquist et al, 2014). It is unclear whether tumor cells invade the lymphatic vessel as a single cell and proceed to grow inside the vessel or whether the cells invade as a “sheet” using collective migration (Friedl & Wolf, 2003).…”

“…For example, colon carcinoma metastasizes to regional LNs and the liver. When implanted in the colonic mucosa in mice, tumor cells metastasized to liver; and systemic, weekly treatment with anti-lymphangiogenic anti-VEGF-C antibody inhibited LN metastasis but did not inhibit liver metastasis (Enquist et al, 2014). …”

Session 2: What causes liver metastases – lymph nodes or is it something else?

“…1) [7]. However, there is very high discordance of 20-40% between lymph nodes and the primary tumour [7]; this is supported by animal models [8].…”