Will colorectal cancer surgery trigger the development of liver metastases?

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Will colorectal cancer surgery trigger the development of liver metastases? New insights into its underlying mechanism

Will colorectal cancer surgery trigger the development of liver metastases?  Surgery is an important means to treat colorectal cancer. However, experimental and clinical evidence indicates that surgery itself may increase the risk of tumor recurrence and/or liver metastasis.

In February 2021, Simran Grewal and others from the University of Amsterdam Medical Center in the Netherlands published a review titled “Surgery for Colorectal Cancer: A Trigger for Liver Metastases Development? New Insights into the Underlying Mechanisms” in Biomedicines. , Summarizes the factors and related evidence that surgery increases the risk of tumor metastasis, and clarifies the triggering role of inflammation in it.

After understanding these mechanisms, relevant interventions can be taken during the perioperative period to reduce the risk of perioperative tumor metastasis, and ultimately improve the long-term survival rate and quality of life of patients. The introduction is as follows:

1. Background

Colorectal cancer (CRC) is the third most common cancer in the world, with more than 1 million newly diagnosed cases in 2018. Tumor metastasis is the main cause of death, and the liver is the most common distant metastasis site, accounting for about 15-25% of newly diagnosed patients. Another 18-25% of patients have distant metastases within 5 years after the first visit.

The treatment plan is determined based on the TNM stage of the tumor, including surgical resection, with or without chemotherapy and/or radiotherapy. The 5-year survival rate of stage I-III CRC is as high as 80%, while that of stage IV CRC is only about 13%. Although surgical removal of the primary tumor can save or prolong life, it is hypothesized that surgery itself may accelerate the development of tumor recurrence and/or liver metastasis.

It has been observed that after breast cancer surgery, 30% of women with negative lymph nodes and 75% of women with positive lymph nodes still develop distant metastases. In the classic tumor metastasis process, tumor cells undergo a complex cascade of events (Figure 1). First, “escape from the primary tumor” to gain mobility and aggressiveness. New blood vessels provide an escape route for tumor cells to enter the blood system.

Secondly, binding to platelets and allowing platelets to cover itself can protect circulating tumor cells (CTCs) from shear stress, immune cells, and the host. Tumor cells need to “stay in a new location”, then colonize to form micrometastasis and finally form macrometastasis. As the metastatic cascade progresses, the number of surviving tumor cells decreases.

Figure 1: The classic way of liver metastasis: the classic way of liver metastasis development. Separate a single tumor cell from the primary tumor (step 1), tumor cell entry into the circulatory system (step 2), systematic transportation of tumor cells (step 3), extravasation of tumor cells into the parenchyma of distant tissues (step 4) , Colonization of distant organs and visible tumor formation (step 5).

2. Adhesion of CTCs

Studies have confirmed that in patients with CRC, the number of CTCs in peripheral and portal vein blood increases during or shortly after surgery, which suggests that surgery can lead to the spread of tumor cells. CTCs have a high independent predictive value for prognosis: patients with >5 CTCs per 7.5 mL of blood have a poor prognosis, and the risk of metastasis within one year increases by 8 times. A recent meta-analysis summarized 20 related studies, including 3687 patients, and provided strong evidence for the prediction of disease progression and survival in patients with non-metastatic colorectal cancer by peripheral blood CTCs. Since CTCs colonization of target organs is a very inefficient process, the spread of tumor cells during surgery may not fully explain the high rate of tumor metastasis.

In order to form metastasis, CTCs first need to adhere to the target organ. Adhesion molecules are expressed on cancer cells and target organ cells and play a key role in the progression of metastasis. The expression of adhesion molecules such as E-selectin, vascular cell adhesion molecule (VCAM)-1 and ICAM-1 increases during liver metastasis. Selectin is a vascular cell adhesion molecule that participates in the adhesion of leukocytes, platelets and endothelial cells in the blood circulation.

Platelets promote tumorigenesis and metastasis through a variety of complementary mechanisms, including aggregation around CTCs to form a “platelet mask”, thereby protecting them from high-shear forces in the bloodstream and immune system attacks, and releasing osmotic factors and degrading enzymes. Assist tumor cells to exudate from the circulatory system. The release of angiogenesis and growth factors also helps promote tumor metastasis.

Selectin is also present in the liver sinusoids and regulates the retention and penetration of CRC cells. In addition, tumor cell-derived factors up-regulate the release of cytokines from immune cells, such as TNFα, IL-1 and IL-6, which enhance the expression of E-selectin on the surface of endothelial cells (including sinusoidal endothelial cells), thereby promoting tumor cell growth. Adhesive and metastatic growth.

Integrins are transmembrane glycoproteins composed of heterodimers of α and β subunits. They mediate cell adhesion and directly bind to ECM components such as fibronectin and collagen. Changes in integrin expression patterns are associated with many types of cancer. Integrins promote the activation and function of ECM proteases by up-regulating the expression of matrix metalloproteinase genes, and participate in the metastatic cascade. The interaction between the heterodimer of integrin and the ECM protein of the target organ leads to the attachment of tumor cells in the liver sinusoids, which ultimately leads to tumor cell extravasation and subsequent organ colonization.

Trauma is inevitable during the resection of the primary tumor. It can trigger a systemic inflammatory response and lead to the rapid activation of immune cells. These cells are powerful producers of inflammatory mediators such as reactive oxygen species (ROS). Experiments have shown that incubating mesothelial cells with ROS can enhance the expression of adhesion molecules ICAM-1 and VCAM-1 to increase the adhesion of tumor cells to mesothelial cells.

In addition, the abdominal wall mesothelium and liver capillaries are damaged after abdominal surgery. This leads to the formation of intercellular spaces and the exposure of extracellular matrix (ECM) proteins-better adhesion sites for tumor cells. Incubation of tumor cells with anti-integrin subunit antibodies can prevent surgically induced tumor cells from adhering and growing in the peritoneum or liver.

3. Anastomotic fistula and bacterial translocation

Approximately 8-10% of patients will develop anastomotic leakage after colon tumor resection. Recent meta-analysis has shown that anastomotic leakage increases the local recurrence rate of colorectal cancer and reduces the long-term survival rate. Colorectal surgery can cause bacteria to migrate into the circulatory system and abdominal cavity.

LPS was detected in the plasma of postoperative patients, and the increase in its concentration resulted in increased intestinal permeability, suggesting that the postoperative intestinal epithelial barrier function was impaired. Similarly, in animal models, it was found that intraperitoneal injection of LPS increased the adhesion of tumor cells to the liver, which could explain the poor prognosis of tumor patients with anastomotic leakage.

4. Surgery leads to activation of immune cells

Bacterial components can effectively trigger the inflammatory immune response by acting on Toll-like receptors (TLRs). LPS is the main ligand of TLR4, and many types of immune cells express TLR4. When the intraoperative bacterial components are released, Kupffer cells (KCs) and polymorphonuclear cells (PMNs) are activated to express TLRs that recognize bacterial products.

This leads to the release of high levels of cytokines and the production of ROS. ROS enhances the expression of mesothelial cell adhesion molecules ICAM-1 and VCAM-1. In addition, in in vitro experiments, exposing the endothelial cell layer to ROS can lead to detachment and reduction of endothelial cells, which subsequently enhances the adhesion of tumor cells to exposed extracellular matrix proteins.

In the experimental rat model, the ROS produced in the body has a destructive effect on the integrity of the liver vascular system, resulting in exposure of ECM components that CTCs can adhere to.

The immune system may be an important factor in determining the prognosis of cancer patients. Based on the quantitative statistics of CD3 and CD8 cells, a scoring system has been developed to classify tumors: “hot” (or “inflammatory”) tumors have a large number of T cell infiltrations, and have a strong adaptive immune system to trigger resistance. Tumor response. In “cold” tumors, T cells are present at the edge of the tumor (exclusion type) or absent (immunosuppressive type), and the host immune system cannot effectively carry out T cell-mediated immune responses.

Therefore, the prognosis of patients with “hot” tumors may be better than that of “cold” tumors. There is no consensus on whether the increase of macrophages in tumors is related to disease-free survival of CRC patients. Macrophages are a double-edged sword in the progression of tumors-they can not only promote tumor clearance, but also stimulate tumor growth. According to different phenotypes, inflammatory macrophages (also known as M1 or classical activated macrophages) are involved in inflammatory response, pathogen clearance and anti-tumor immunity.

In contrast, immunomodulatory macrophages (also known as M2 or alternative activated macrophages) are associated with immunosuppressive response, wound healing, and promotion of tumor growth, including induction of angiogenesis and promotion of metastasis.

The imbalance of postoperative pro-inflammatory and anti-inflammatory immune responses may weaken anti-tumor cytotoxicity, or promote immune regulation and wound healing, thereby promoting metastasis. Intraoperative and postoperative acute phase reactions trigger systemic inflammatory reactions, leading to rapid activation of innate immune cells, followed by increased cytokine production. The cytokines that play a leading role in the formation of distant metastasis such as tumor necrosis factor (TNF)α, IL-1 and IL-6 are released after surgery.

These cytokines can increase the adhesion of tumor cells by enhancing the expression of adhesion molecules. In order to balance the effects of the acute phase response, compensatory anti-inflammatory mediators are released. In immunodeficient mice and patients receiving immunosuppressive therapy, the unbalanced systemic compensatory anti-inflammatory response may make patients vulnerable to infection after surgery and weaken anti-tumor immunity. In short, “surgery-induced liver metastasis” represents another metastasis approach that starts intraoperatively and postoperatively, which shortens several steps in the classic metastasis model. (Figure II)

Figure 2: Surgery-induced liver metastasis: Surgical resection of primary colorectal cancer (step 1) results in the release of bacterial products (LPS) and tumor cells (step 2). The systemic transport of tumor cells (3) and the activation of ROS-producing Kupffer cells and polymorphonuclear cells (4) lead to the exposure of subendothelial extracellular matrix.

5. Interventions to prevent metastasis during the perioperative period

(1) Limit the size of surgical trauma?

Surgery removes the tumor burden but increases the chance of CTCs adhesion. Therefore, the biggest challenge is not to remove the tumor but to prevent tumor metastasis. In animal experiments, more tumor cells adhered to the liver of rats in the colectomy group compared with the control group or the laparotomy group (sham operation group). This suggests that reducing tissue damage may improve patient prognosis. At present, laparoscopic surgery is the first choice for the treatment of CRC due to its low intraoperative bleeding, quick postoperative recovery, less pain, and short hospital stay, but it is not clear whether it is beneficial to the tumor outcome.

An early study conducted by Lacy et al. included 219 patients and compared the efficacy of laparoscopic-assisted and open colectomy in terms of tumor recurrence and survival. The results showed that the overall survival rate of patients with laparoscopic-assisted colectomy was higher than that of open surgery. However, this study is controversial because these results can only be reproduced in a subgroup of patients in two recent large trials, namely the Barcelona trial and the laparoscopic or open colorectal cancer resection (COLOR) trial.

The Barcelona trial found that the cancer-related mortality of the laparoscopic assisted group was significantly lower than that of the open surgery group, p = 0.03. However, this difference was caused by the results of the subgroup of stage III patients; in the COLOR II trial, the two groups of patients were 3 years after surgery The long-term local recurrence rate is 5%. However, for the treatment of tumors in the lower third of the rectum, the local recurrence rate of laparoscopic surgery is lower than that of open surgery, and the 3-year disease-free survival rates were 74.8% and 70.8%, respectively, and the difference was not statistically significant. Therefore, excluding certain subgroups, laparoscopic surgery may not be better than open surgery in terms of the overall prognosis of cancer patients.

(2) Reduce inflammation

In animal models, ROS scavenger treatment initially reduced the adhesion of tumor cells, but it promoted the growth of liver metastases, possibly because ROS played a role in the killing of tumor cells by macrophages. The development of a short half-life ROS scavenger therapy to inhibit the production of early ROS, reduce liver vascular damage and tumor cell adhesion, while retaining the long-term function of macrophages is the future research direction. The perioperative use of COX inhibitor therapy (blocking catecholamines and/or prostaglandins) on the survival rate is uncertain.

(3) Oral antibiotics to purify the digestive tract

The microorganisms in the human digestive tract constitute the microbial ecosystem. In recent years, DNA and RNA sequencing technologies have shown that the diversity and metabolic interaction of microbial communities have a great impact on the development of infections and diseases. When the intestinal balance is disrupted, potentially pathogenic microorganisms can promote the occurrence of diseases and infectious complications, such as surgical site infection (SSI) and anastomotic leakage (AL). Selective Decontamination of the Digestive Tract (SDD) is the removal of potentially pathogenic microorganisms (mainly aerobic gram-negative bacteria, Staphylococcus aureus and fungi) in the intestines through oral administration of non-absorbable antibiotics , To minimize the impact of endogenous infections. In 2009, Roos and other RCT studies showed that the incidence of infectious complications and anastomotic leakage in patients undergoing various gastrointestinal surgeries treated with SDD was significantly reduced. Recently, the results of the ELECT multi-center randomized controlled trial showed that: SDD reduced the infectious complications after colorectal cancer resection, but did not significantly reduce the anastomotic leakage. A systematic review and meta-analysis showed that preoperative oral antibiotics (OAB) combined with mechanical bowel preparation (MBP) and standard intravenous prophylactic antibiotics significantly reduced the incidence of SSI and AL in patients undergoing elective colorectal cancer resection.

Figure 3: The number of tumor cells per field of view (fov) in the liver of rats treated with SDD, simple anesthesia, laparotomy or colectomy. ** p <0.01.

Expert Comments: 

At present, many experimental and clinical evidences support this view: surgery as a treatment method will promote tumor metastasis. In this review, the authors emphasized that bacterial products and inflammatory reactions caused by surgical trauma may be potential factors leading to poor prognosis in cancer patients.

In view of the fact that the perioperative period is a “window of opportunity” to reduce the risk of tumor metastasis, the author advocates speeding up relevant research to determine effective interventions during the perioperative period, such as selective decontamination of the digestive tract (SDD).

It is also mentioned in Chapter 196 that how to reduce the risk of metastasis in cancer patients through perioperative interventions has always been a hot issue for clinicians. However, the complexity and diversity of perioperative confounding factors make the design and implementation of trials not easy, but it undoubtedly has a huge effect on improving the prognosis of patients with malignant tumors worldwide.

Surgery is a vital intervention, providing cancer patients with a chance to be cured. The perioperative period is characterized by the accelerated growth of micrometastasis and the increased risk of new metastases formation. Surgery can induce cancer cells to fall off and enter the circulation to increase, inhibit anti-tumor immunity, make circulating tumor cells survive, up-regulate adhesion molecules in target organs, recruit immune cells that can block tumor cells, and induce changes in target tissues and cancer cells themselves.

To enhance the establishment of migration and invasion at the target site. Surgical trauma induces local and systemic inflammatory reactions, and can also lead to the accelerated growth of residual and micrometastasis disease. Other perioperative factors such as anesthesia, blood transfusion, hypothermia and postoperative complications may also be harmful factors leading to early recurrence.

With limited understanding of these processes, we can transform the perioperative time frame from the main facilitator of metastatic progression to the window of opportunity to prevent and/or eliminate residual disease, thereby potentially improving the long-term survival of cancer patients.

(source:internet, reference only)

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