Surgery is unanimously regarded as the primary strategy to cure solid tumors in the early stages but is not always used in advanced cases. However, tumor surgery must be carefully considered because the risk of metastasis could be increased by the surgical procedure. Tumor surgery may result in a deep wound, which induces many biological responses favoring tumor metastasis. In particular, NETosis, which is the process of forming neutrophil extracellular traps (NETs), has received attention as a risk factor for surgery-induced metastasis. To reduce cancer mortality, researchers have made efforts to prevent secondary metastasis after resection of the primary tumor. From this point of view, a better understanding of surgery-induced metastasis might provide new strategies for more effective and safer surgical approaches. In this paper, recent insights into the surgical effects on metastasis will be reviewed. Moreover, in-depth opinions about the effects of NETs on metastasis will be discussed.
Surgical resection of tumor masses has been regarded as the primary strategy to effectively eradicate cancer cells. Even in cases of incurable cancers, surgery is often performed to prolong the patient’s lifespan or to relieve cancer pain and some complications associated with tumor masses1. However, a wide range of unwanted effects are related to these procedures. In addition to general complications, such as bleeding, thromboembolism, and wound infection, surgery per se can promote cancer metastasis through a series of local and systemic events2,3. A growing body of evidence from clinical and experimental studies has suggested that surgery results in a serious wound that disrupts the structural barrier preventing the outspreading of cancer cells, change the properties of the cancer cells and stromal cells remaining in the tumor microenvironment, or impairs the host defense systems against cancers4,5,6. Consequently, these unwanted effects of surgery can trigger the second phase of tumor recurrence and metastasis, which are newly acquired events, rather than just outcomes of incomplete treatment. In particular, infection and inflammation during the postoperative period have been reported to increase the risk of cancer recurrence in patients7,8,9. Notably, these unwanted effects are only found in some patients, not all. Given that the prognostic benefits of surgery are generally greater than the disadvantages, surgical resection should not be abandoned. Nonetheless, it is worthwhile to fully elucidate the mechanisms underlying surgery-triggered aggravation of cancer because it could provide new strategies for more effective and safer surgical approaches for cancers. In this paper, two topics on surgery-triggered cancer metastasis will be discussed. One is a general review concerning the local and systemic influences of cancer surgery on metastasis; the other is the in-depth review concerning the unique role of neutrophils in cancer metastasis.
Surgery-induced cancer metastasis
Surgeons have long suspected that surgery, even if it is a necessary step in cancer treatment, facilitates cancer metastasis3. This issue remains an unsolved question. Surgery-induced cancer metastasis has been well established in animal models, such as tumor grafts and spontaneous tumorigenesis10,11,12. As many clinical studies have shown an increased incidence of metastasis during the perioperative period, this event also seems to occur in patients with advanced cancers13,14. However, whether the surgical resection of primary tumors is beneficial is controversial. A number of perioperative changes, including tumor cell dissemination, tumor-favoring immune responses, and neoangiogenesis, have been proposed to explain surgery-induced metastasis15,16. This scenario is summarized in Fig. 1.
Tumor cell release by surgical injury
As the tumor cells in the vessels can circulate around the body, they are called circulating tumor cells (CTCs). The number of CTCs is generally viewed as a reliable marker indicating poor outcomes for cancer patients because it is closely associated with tumor metastasis17,18,19,20,21,22,23,24. Moreover, many lines of evidence suggest that CTCs abruptly increase just after surgery25,26,27,28. While solid tumors are surgically removed, the tumor architecture is inevitably destroyed due to physical insult, which raises the chance for tumors to shed their cells into the lymphatic and blood vessels. Even externally palpitating tumors for diagnosis could increase the numbers of CTCs in skin cancer and breast cancer27. However, how significantly surgery-induced CTC release impacts patient prognosis is still controversial. It is not surprising that the CTC number can increase during the perioperative period. However, the CTC number may be dependent on the tumor volume remaining after surgery. It is eventually reduced after complete resection of CTC-releasing tumors but not after incomplete resection25. During surgery, the dissemination and intravasation of tumor cells might be attributed to mechanical pressure and vascular injury29. Long after surgery, tumor cells may spread due to increased cell migration and vascular permeability in the altered microenvironment13,30,31.
Immunity altered by surgical stress
Surgical wounds trigger inflammatory responses to favor survival and extravasation of CTCs28,32,33. Surgery can disturb the balance between the innate and adaptive immune systems, leading to impaired surveillance of tumors34,35. Such an effect on surgery seems to be responsible for the systemic response to stress, including the activation of the hypothalamic–pituitary–adrenal (HPA) axis and subsequent production of stress hormones36,37. Upon HPA stimulation, corticotrophin-releasing hormone (CRH) is secreted from the paraventricular nucleus in the hypothalamus and then stimulates the secretion of adrenocorticotropin hormone (ACTH) from the anterior pituitary. The secreted ACTH induces the synthesis and release of glucocorticoids in the adrenal cortex38. As excessive glucocorticoids negatively modulate immune functions, immune surveillance against tumors is considered to be impaired by surgical stress, thereby facilitating the growth of tumors remaining around surgical wounds and metastatic tumors at distant sites39,40,41.
In addition to glucocorticoids, during stimulation of the HPA axis, the catecholamine hormones epinephrine and norepinephrine are released from the adrenal medulla42,43. Adrenergic receptors (ARs) for these hormones are located on the surface of immune cells. Many studies have shown that α- and β-ARs are both expressed by innate immune cells, including neutrophils, monocytes, macrophages, dendritic cells, and NK cells44,45,46,47,48. In particular, β2-AR is an AR subtype expressed at the highest level on both innate and adaptive immune cells. Therefore, β2-AR is regarded as the main mediator responsible for the immune effects of catecholamines49,50,51,52.
We first review how adrenergic signaling affects innate immunity. β2-AR signaling promotes the M2 differentiation of macrophages, subsequently leading to inhibited production of pro-inflammatory cytokines. In contrast, α-AR signaling has been shown to reverse the effect of β-AR signaling in macrophages53,54,55,56,57,58. In dendritic cells, β2-AR signaling inhibits their differentiation and antigen presentation function. This signaling also suppresses the production of the pro-inflammatory cytokines IL-12 and TNF-α from dendritic cells, whereas it enhances the production of the anti-inflammatory cytokines IL-6, IL-10, and IL-3349,59,60,61. In NK cells, their cytotoxic activity and IFNγ production have been found to be substantially reduced after primary tumors are removed62,63. This NK cell suppression may be attributed to increased levels of catecholamines as well as glucocorticoids64,65,66. However, the role of adrenergic signaling in the antitumor activity of NK cells is still controversial because it may differ depending on the type and duration of stress67,68,69. Moreover, there are many reports investigating the adrenergic modulations of other innate immune cells. For example, β2-AR stimulation has been reported to functionally inhibit eosinophils and subsequently aggravate asthma70.
In contrast, adrenergic signaling can suppress adaptive immunity. For instance, β-AR signaling decreases the numbers of thymocytes through negative selection in the thymus by activating the p38 signaling pathway71. In addition, adrenergic signaling decreases the production of IL-2 and IFN-γ by CD4+ T cells and prevents their proliferation. This signaling also regulates Th1 and Th2 differentiation. β2-AR activation was found to promote CD4+ T-cell polarization toward a Th2 phenotype72,73,74,75,76. In memory and effector CD8+ T cells, which express β2-AR at a higher level than naive T cells, β2-AR signaling downregulates IL-2 and IFN-γ expression under stimulation77,78. In regulatory T cells (Tregs), however, β2-AR signaling enhances immune-suppressive activity by inducing CTLA-4 and Foxp3 expression72,79. The in-depth discussion about this subject is omitted because it is beyond the scope of this review.
Angiogenic state altered by removal of primary tumors
A striking hypothesis about angiogenic competition among tumors was experimentally tested by Dr. Folkman and his colleagues80. In mice bearing a primary tumor, it was observed that the removal of the primary tumor facilitated the growth of highly vascularized metastases. For hypothetical mechanisms, primary tumors may secrete angiogenic inhibitors as well as angiogenic activators. In the microenvironment of the primary tumor, the activators are abundant enough to overwhelm the inhibitors. In the systemic circulation, however, the activators quickly decay, whereas the inhibitors remain stable. Consequently, small metastases at distant sites are affected to a greater extent by angiogenic inhibitors than by activators, leading to the dormancy of metastases due to limited vascularization. After the primary tumor is surgically removed, the metastases can start to grow vigorously via neoangiogenesis because the circulating inhibitors disappear. Angiostatin and endostatin are regarded as representatives of tumor-derived angiogenesis inhibitors81,82,83.
Roles of netosis in surgery-induced cancer metastasis
Neutrophils are the most abundant type of granulocytes, comprising 40–70% of all white blood cells. These cells neutralize invading microorganisms and act as the main mediators of inflammation. They rapidly accumulate in inflamed areas, where they undergo highly diverse reactions84,85,86,87. These cells not only play defensive roles against harmful microorganisms but also clear dead cells for tissue regeneration88,89,90. However, since neutrophils also play harmful roles in many inflammation-associated diseases, they are considered a double-edged sword91. In addition, neutrophils play various roles in the initiation and progression of cancer92,93,94. In particular, a unique phenomenon named NETosis has been intensively investigated as a pathogenic event in many inflammatory and neoplastic diseases95,96,97,98,99,100,101. NETosis refers to the formation of neutrophil extracellular traps (NETs), which are large extracellular complexes composed of chromatin and cytoplasmic/granular proteins102,103. Recently, NETosis has been highlighted as an inflammatory event that promotes cancer metastasis104,105.
NETs and NETosis
Neutrophil extracellular traps (NETs), which were first identified by Volker–Brinkmann and Arturo–Zychlinsky, are fishing net-like structures that can entrap microorganisms invading blood and tissues86. Once activated, neutrophils produce intracellular precursors by using DNA, histones, and granular and cytoplasmic proteins and then spread the mature form of NETs out around themselves. A series of these events is called NETosis. In NETs, the following proteins are included: neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, lactoferrin, gelatinase, lysozyme C, calprotectin, neutrophil defensins, and cathelicidins106,107,108,109,110. As NETs contain a high content of DNA threads, they are sticky enough to entrap and immobilize microorganisms and then kill them using lethal enzymes. Therefore, NETosis is currently defined as an innate immune response against infection. In addition to its antimicrobial activity, NETosis plays a pivotal role in noninfectious autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis96,99,111. Moreover, NETosis is involved in other inflammatory diseases, such as vasculitis, intravascular thrombosis, atherosclerosis, periodontitis, and diabetes112,113,114,115,116.
Although the precise mechanisms underlying NETosis are still being investigated, some of the molecular pathways have been identified in two types of NEToses, suicidal (or lytic) NETosis and vital NETosis117. Suicidal NETosis mainly depends on the production of reactive oxygen species (ROS)102. Many stimuli, such as phorbol 12-myristate 13-acetate (PMA), bacterial endotoxins, and interleukins, have been found to induce suicidal NETosis. Indeed, PMA and IL-8 are widely used to induce suicidal NETosis in vitro86,102. Alternatively, suicidal NETosis can be induced by antibodies (especially the Fc region) binding to specific receptors on the surface of neutrophils118. Following the stimulation of neutrophils, protein kinase C (PKC) is activated via diverse pathways and in turn activates the Raf-MEK-ERK signaling cascades, followed by ROS production from NADPH oxidases119,120. Alternatively, IL-8 enhances the cytoplasmic levels of ROS, which are mediated by the following process: NF-κB activation via the CXCR2-PI3K-AKT pathway and iNOS and COX2 induction by NF-κB121,122,123. Then, ROS play central roles in suicidal NETosis because they induce the release of the serine protease neutrophil elastase (NE) and myeloperoxidase (MPO) from azurophilic granules and activate peptidyl arginine deiminase 4 (PAD4). PAD4 citrullinates histones in the presence of calcium ions, leading to chromatin decondensation124,125. After the nucleus becomes deformed and ruptured, the decondensed chromatin is released to the cytoplasm and entangled with proteolytic enzymes and other proteins, which are the intracellular precursors of NETs126. Finally, the intracellular NET complexes are released through a broken part of the plasma membrane. Since neutrophils die during this process, it is called suicidal NETosis.
However, there is another type of NETosis called vital NETosis. Compared with suicidal NETosis, vital NETosis occurs independently of ROS production from NADPH oxidase127. Vital NETosis can be induced by Gram-negative bacteria. LPS in the outer membrane of the bacteria interacts with Toll-like receptor 2 (TLR2) on neutrophils and TLR4 on the surface of platelets, which triggers NETosis128. The stimulation of these receptors increases the cytoplasmic level of Ca2+ and subsequently stimulates PAD4, leading to NET formation. As NETs are entrapped within vesicles, neutrophils can release them without membrane rupture. The neutrophils undergoing this type of NETosis are still alive, so this process is called vital NETosis. However, the signaling pathway responsible for vital NETosis remains unclear. The molecular mechanisms underlying NETosis are summarized in Fig. 2.
NETosis in the tumor microenvironment
Experimental and clinical studies have revealed that NETs are present in a variety of cancers, such as lung cancer, colon cancer, ovarian cancer, and leukemia129,130,131,132,133. This finding suggests that neutrophils actively undergo NETosis in the tumor microenvironment. To date, several hypotheses have been proposed to explain why NETosis is stimulated within tumors. Hypoxia could be one of the reasons because it often develops in growing solid tumors and robustly induces the transcription factor HIF-1. Indeed, McInturff et al. (2012) demonstrated that HIF-1 in neutrophils plays a critical role in NETosis and bacteria-killing activity134. Some cytokines enriched in the tumor microenvironment may stimulate tumor-infiltrating neutrophils to undergo NETosis. For instance, the pro-inflammatory cytokines IL-8, IL-17, G-CSF, CXCL5, and CXCL6 are released from tumor cells and recruit neutrophils in the bone marrow to tumor regions135,136,137,138,139,140. Moreover, many recent reports have suggested that most cytokines potentially initiate or facilitate NETosis in vitro or in vivo141,142,143. In addition to cytokines, some tumor-derived proteases and tumor exosomes have been reported to induce NETosis144,145. Therefore, NETosis generally actively progresses in the tumor microenvironment.
Recently, NETosis has been investigated as an emerging surrogate marker for cancer diagnosis. The plasma levels of NETs were found to be higher in patients with several types of tumors, including lung cancer, pancreatic cancer, and bladder cancer, than in healthy controls146. In lung cancer patients, NETs are present in lung tissues and are also detected in peripheral blood and sputum130. In the case of colon cancer, neutrophils from cancer patients were found to undergo NETosis at a higher level under in vitro stimulation than those from healthy controls147. Interestingly, such in vitro results positively correlated with the poor clinical outcomes of the patients. Moreover, immunofluorescence staining showed that some components of NETs were detected at the highest level in metastases originating from breast and colon cancers148. Recently, a clinical study demonstrated that the serum levels of NET components at the preoperative stage were associated with poor survival in cancer patients149. Given these reports, the plasma levels of NET components could be emerging biomarkers to predict the clinical outcomes of cancer patients.
To date, NETosis can be estimated by detecting molecular markers, such as extracellular DNA, citrullinated histone 3 (Cit-H3), and neutrophil-derived protein complexes. However, most researchers tend to confirm this process using more than two markers because each marker has low reliability. Nonetheless, immunochemistry using an anti-Cit-H3 antibody is regarded as a standard method because H3 citrullination is very specific to NETosis. However, even Cit-H3 immunostaining has some drawbacks in use because the procedure is difficult, time-consuming, and not applicable to real-time monitoring. Recently, a research team successfully developed a new NET detection method using the extracellular DNA-intercalating dye CDr15150. This method was found to be easier than previous methods and applicable to the real-time tracing of NETosis. Considering the clinical importance of NETosis, it is worthwhile to develop new NET-detecting materials that are applicable to experimental and clinical studies.
Neutrophil activation and NETosis following surgical injury
Surgical trauma and subsequent complications, including wound infection, increase neutrophil counts in the peripheral blood through increased granulopoiesis in the bone marrow151,152,153,154. Additionally, tissue injury affects the function of circulating neutrophils155,156. The changes in neutrophil functions depend on the micromilieu of the damaged tissue. In wounds, damaged and necrotic cells express the signals responsible for early neutrophil recruitment, which are damage-associated molecular patterns (DAMPs)157,158,159,160. DAMPs are cellular components including DNA, histones, ATP, interleukin-1α, high mobility group protein B1 (HMGB1), N-formyl peptides, and others. DAMPs directly activate neutrophils through G-protein-coupled receptors161,162. Indirectly, DAMPs can stimulate surrounding tissues to produce chemokines and lipid mediators for neutrophil chemotaxis163,164. In wounds, neutrophils clear necrotic cells and invading microorganisms165,166,167. Moreover, they release various cytokines responsible for tissue repair168,169. Indeed, neutrophils express and store a variety of growth factors and angiogenic factors that contribute to regeneration and revascularization170,171. For example, the proliferative cytokines TGFβ and IL-10 and the angiogenic factor VEGF are representative of neutrophil-derived tissue repair proteins.
As mentioned above, NETosis is a defense system to protect the body from invading pathogens172. However, when neutrophils are excessively stimulated, they produce excess NETs, thereby leading to pathological consequences173,174. To eliminate a visceral tumor, surgeons make a deep incision on the skin, remove a part of the tumor-bearing organ, and reconstruct surrounding tissues for functional recovery. Since such a procedure involves large wounds, it can induce severe inflammation and subsequently stimulate neutrophils to undergo NETosis. Given many clinical reports showing that the plasma levels of NETosis markers are elevated after major surgeries, NETs formed at surgical wounds are believed to circulate throughout the body along with blood and lymphatic streams175,176,177,178. Since NETs circulate in the peripheral blood, the components of NETs could be surrogate markers for evaluating the progression of cancers in clinical settings179,180,181,182.
Roles of NETs in tumor metastasis
Metastasis refers to tumor cell spread out of the original location and the formation of secondary lesions at distant sites. Tumor cells metastasize through the following sequences: local invasion, intravasation into the blood or lymphatic vessels, escape from the immune system, anchoring to capillaries in target organs, extravasation into the organs, transformation from dormant cells to proliferating cells, colonization to micrometastases, and growth to macrometastases183,184,185,186,187,188,189. Many lines of evidence suggest that NETs promote metastasis at multiple steps, which are summarized in Fig. 3.
NETs promote the local invasion of cancer cells by degrading the extracellular matrix (ECM)190,191. ECMs, which are mainly composed of fibrous proteins and polysaccharides, act as a barrier blocking cell movement, and thus, degrading the ECM is essential for tumor cell invasion192. As mentioned previously, NETs contain many proteolytic enzymes, such as neutrophil elastase, matrix metalloproteinase 9, and cathepsin G. These NET enzymes loosen the ECMs to allow cancer cell movement. NETs also promote the intravasation of cancer cells by increasing vascular permeability193. The wall of a capillary consists of two layers: the endothelial layer and the outer basement membrane (mainly made of connective tissues). Capillaries (especially, continuous capillaries) are characterized by a complete endothelial lining with tight junctions between endothelial cells. The tight junction is impermeable to macromolecules but allows the passage of small molecules, such as water, ions, gases, metabolites, and hormones. Therefore, cancer cells should penetrate the two layers to enter the circulation, which cannot occur normally. Given that the basement membrane and the tight junction are both mainly composed of proteins, it is not surprising that protease-containing NETs loosen the vascular wall and allow cancer cells to penetrate into the vessel. Moreover, pro-inflammatory cytokines released from activated neutrophils escalate the enhancement of vascular permeability194.
Even if cancer cells successfully enter the circulation, only a few of them can survive to finally establish metastases. Indeed, millions of tumor cells are released into the circulation every day, but metastases are not observed as frequently as we estimate. There are two obstacles that circulating tumor cells (CTCs) need to overcome: the shearing force by blood flow and the immune system. NETs can wrap up CTCs with platelets owing to their sticky jelly-like properties195. By doing so, NETs can act as armor to protect CTCs from the shearing force and the attack of immune cells. Najmeh et al. also suggested that β1-integrin plays an important role in the interaction between CTCs and NETs196. In case of tumor surgery, neutrophils and platelets can be simultaneously activated, which facilitates the formation of NET-platelet-CTC aggregates.
Finally, the CTC aggregates stop traveling to some capillaries in distant organs because they are too sticky and large to continuously circulate. The CTC aggregates are entrapped in or adhered to the inside walls of capillaries and in turn extravasate into the parenchyma to establish new colonies. The termination of this journey may be a new focus of metastasis. In the growth of micrometastases, the involvement of NETs has been demonstrated in several animal studies. For instance, when tumor-bearing mice were injected with DNase (decomposing NETs), the growth of the preexisting metastases was significantly retarded180. In mice subjected to abdominal surgery, NETs in the peritoneum collected tumor cells and provided a microenvironment favoring tumor survival and growth. These results suggest that NETosis is a potential target to prevent surgery-induced tumor metastasis.
After metastasizing to distant tissues, tumor cells are often found to remain dormant for a period of time and unexpectedly regrow later197. To date, little is known about the molecular mechanisms underlying tumor dormancy and reactivation. In addition to the metastatic process, NETs are believed to participate in the reactivation of dormant cancer cells in metastatic regions198. An animal study showed that dormant micrometastases became aggressively growing metastases after lung inflammation was induced by tobacco smoke or nasal instillation of lipopolysaccharide. In this study, the NET-associated proteases NE and MMP-9 were found to be responsible for the reactivation of dormant cancer cells. Laminin cleavage by enzymes may induce reactivation through the integrin α3β1 signaling pathway. However, the effects of NETs on the reactivation of dormant cells remain uncertain.
Here, we discuss how distant metastasis paradoxically increases after resection of the primary tumor. From two points of view, this topic was discussed: one is a general review concerning surgery-triggered metastasis; the other is a review concerning the roles of NETs in metastasis. After surgical removal of tumors, the tumors and surrounding tissues are harshly handled, which increases the chance for tumor cells to spread. Because the surgery results in a deep wound, it might provoke systemic stress, which inhibits immunity against tumor cells. Moreover, as small metastases can escape from the angiogenic control of the primary tumor, they can grow vigorously after tumor surgery and are clinically detected as multiple metastases. Second, we discuss recent advances in tumor- and surgery-induced NETosis. NETosis is an innate immune process that entraps and kills microorganisms, but it also plays a pathogenic role in many inflammatory diseases. Neutrophils are activated and subsequently undergo NETosis in the tumor microenvironment and the surgical wound, both of which are enriched with pro-inflammatory cytokines. Furthermore, many reports have suggested that NETs stimulate the entire metastatic process from local invasion of cancer cells to colonization/growth. Therefore, NETosis could be an emerging target for blocking tumor metastasis after tumor surgery.
In fact, surgery is a very complicated procedure because it is accompanied by many medications for anesthesia, analgesia, muscle relaxation, and infection control. Obviously, these medications during the perioperative period should be considered risk factors that may affect tumor metastasis. Nonetheless, we restrictively focused on the effects of surgical procedures and wounds on tumor cell spreading and metastasizing to distant organs. Considering that surgery-related medications are doctors’ most likely options, we can try to substitute safer drugs for metastasis-inducing drugs. We hope that this topic will be discussed in future studies.
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J.-W.P. was supported by the Education and Research Encouragement Fund of Seoul National University Hospital.
The authors declare no competing interests.
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Kwak, SB., Kim, S.J., Kim, J. et al. Tumor regionalization after surgery: Roles of the tumor microenvironment and neutrophil extracellular traps. Exp Mol Med 54, 720–729 (2022). https://doi.org/10.1038/s12276-022-00784-2