Myeloid tumor necrosis factor and heme oxygenase‐1 regulate the progression of colorectal liver metastases during hepatic ischemia‐reperfusion

Abstract

The liver ischemia‐reperfusion (IR) injury that occurs consequently to hepatic resection performed in patients with metastases can lead to tumor relapse for not fully understood reasons. We assessed the effects of liver IR on tumor growth and the innate immune response in a mouse model of colorectal (CR) liver metastasis. Mice subjected to liver ischemia 2 days after intrasplenic injection of CR carcinoma cells displayed a higher metastatic load in the liver, correlating with Kupffer cells (KC) death through the activation of receptor‐interating protein 3 kinase (RIPK3) and caspase‐1 and a recruitment of monocytes. Interestingly, the immunoregulatory mediators, tumor necrosis factor‐α (TNF‐α) and heme oxygenase‐1 (HO‐1) were strongly upregulated in recruited monocytes and were also expressed in the surviving KC following IR. Using TNFflox/flox LysMcre/wt mice, we showed that TNF deficiency in macrophages and monocytes favors tumor progression after IR. The antitumor effect of myeloid cell‐derived TNF involved direct tumor cell apoptosis and a reduced expression of immunosuppressive molecules such as transforming growth factor‐β, interleukin (IL)‐10, inducible nitric oxyde synthase (iNOS), IL‐33 and HO‐1. Conversely, a monocyte/macrophage‐specific deficiency in HO‐1 (HO‐1flox/flox LysMcre/wt) or the blockade of HO‐1 function led to the control of tumor progression post‐liver IR. Importantly, host cell RIPK3 deficiency maintains the KC number upon IR, inhibits the IR‐induced innate cell recruitment, increases the TNF level, decreases the HO‐1 level and suppresses the tumor outgrowth. In conclusion, tumor recurrence in host undergoing liver IR is associated with the death of antitumoral KC and the recruitment of monocytes endowed with immunosuppressive properties. In both of which HO‐1 inhibition would reinforce their antitumoral activity.

Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53

“…We next investigated the mechanism by which HO-1 could induce stemness in CRC. As mentioned before, HO-1 could modulate ET-1 production in several models of health and disease [37][38][39][40][41].…”

“…In the recent years, numerous research works have tried to elucidate the role of HO-1 in colorectal cancer. This has not been an easy task, since this enzyme is found in both cancer and stromal cells, including immune cells [38][39][40][41]. In addition, HO-1 in CRC cells is able to regulate immune-mediated cytotoxicity against CRC cells [18].…”

Targeting hepatocyte MagL regulates the progression of colorectal liver metastases during liver ischemia-reperfusion

“…Many clinical studies have demonstrated that LIR is associated with poor prognosis of postoperative CRC recurrence (7,8,30). Many research teams have also reached the same conclusion in murine models (12,16,31). Overall, the changes brought about by LIR on the hepatic microenvironment have a synergistic effect on the development of tumors.…”

Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3

“…IR indury during liver resection has been shown to accelerate liver cancer progression, while severe residual liver ischemia is associated with reduced cancer-specific survival rates [10]. IR injury during liver surgery has been shown to accelerate the progression of colorectal liver metastases (CRLM) in animal models [11][12][13][14].…”