Surgical intervention paradoxically enhances micrometastasis – targeting perioperative variables

Dear Editor,

Surgery plays a crucial role in the treatment of cancer, and ~60% of cancer patients undergo some form of surgical intervention. Micrometastases and the development of new metastatic foci are more likely to progress rapidly during the perioperative period. In order to invade and thrive at a new metastatic location, a cancer cell must first enter the circulation, then endure the host’s defensive systems, then get imprisoned at a regional or distant site. However, metastasis as a whole is inefficient, and most cancer cells that make it into the bloodstream are promptly eliminated¹. Besides careful dissection performed by surgeons, like any other kind of tissue damage, may trigger a systemic and local inflammatory response that may help the cancer cell survive and spread.

It has been proven that tumor cells are lost into the blood and lymphatic circulation during resection due to the inevitable injury to the patient’s tissues during excision and manipulation of the tumor being excised and its vasculature². In addition, the number of cancer cells that are circulating in the blood before and after surgery is an excellent predictor of recurrence². Dissemination of circulating cells is just part of the problem; various postoperative modifications aid cancer cell survival in circulation and boost the possibility of distant implantation. Both macrophages and natural killer cells are essential in the fight against metastatic cancer and its spread throughout the body².

The release of neutrophils after surgical stress seems to aid in tumor encapsulation and progression³. In response to tissue damage, neutrophils release a web-like DNA structure called a neutrophil extracellular trap (NET) that may capture migrating tumor cells. DNA strands are studded with a range of proinflammatory chemicals that are essential for the capture of tumor cells and the enhanced proliferation of metastases in surgically modified livers³. Surgeons can significantly slow the progression of new metastatic diseases by targeting NETs. The more serum evidence of NET formation after the excision of hepatic colorectal metastases in people, the higher the risk of recurrence^3,4. Therefore, the environment created following tumor removal may alter long-term outcomes associated with cancer, as shown by both experimental and clinical studies.

Primary solid tumors of the digestive tract have an unusually high propensity to metastasize to the liver. Surgical trauma is one possible cause since it might diminish the expression of tight junction proteins in liver endothelial cells, allowing cancer cells to more easily invade the liver parenchyma^4,5. The production of catecholamines and prostaglandins, as well as the formation of NETs in response to surgical stress, might increase tumor cell migration and invasion into a distant organ, hence promoting the metastatic potential of the attached circulating cancer cells^4,5. Thus, surgical damage in the hepatic-gastrointestinal watershed synchronizes the increased numbers of circulating cancer cells, the reduced antitumor immunity, and the pro-metastatic milieu of the targeted organs.

It is possible for metastatic cancer cells to break out from the main tumor at an early stage and generate micrometastases at distant places. These islands of micrometastases might lie quiescent, stuck somewhere between cell division and cell death⁶. Their development potential may be unexpectedly unlocked by the local and systemic inflammatory processes that accompany surgical trauma⁶. The excision of the original tumor may loosen the inhibitory control provided by primary tumors, which acts to keep the development of latent metastases in check, in addition to the soluble substances that stimulate distant tumor growth following surgery. Both proangiogenic agents and inhibitors of angiogenesis are secreted by primary tumors. As long as new blood vessels, critical to the tumor’s continued expansion, are present in the main tumor’s microenvironment, the inducers will always triumph over the inhibitors. However, when released into the bloodstream, the levels of the more labile inducers soon decline, whilst the levels of the more stable inhibitors produce a systemic antiangiogenic milieu that limits the induction of neovascularization and growth of tiny, distant micrometastases. This causes the micrometastases to stay tiny and inactive. Once the initial tumor is gone, inhibitor levels drop and the metastatic spread resumes with full force. The systemic levels of antiangiogenic factors such angiostatin, endostatin, and thrombospondin^4,7 may be reduced after a tumor has been surgically removed, allowing the angiogenic switch to be turned on. Therefore, the decreased expression of antiangiogenic factors, together with the increases in the levels of growth factors and proangiogenic chemicals generated by surgery, may allow for the angiogenic switch and rapid progression of otherwise undetected latent micrometastatic illness^4-7.

Postoperative downregulation of the adaptive immune response may potentially contribute to immunological escape. For instance, once a tumor has been removed, the number of circulating dendritic cells, which play a crucial role in immune surveillance, naturally declines. Adding dendritic cell vaccination to tumor-bearing mice before surgery greatly reduces the development of the tumor^8,9. Additionally, human T helper 1 (Th1) functions are compromised after surgery⁸. Reduced antitumor cytotoxicity may also result from impaired Th1 responses, which are critical for specific cellular immunity and the expansion of cytotoxic T cells. In addition, surgery activates Stat3 and NF-kappaB pathways^3,4, leading to neutrophil recruitment and NET formation at the site of damage, which may last for weeks and promote the development of residual illness. Therefore, the time before surgery might be a phase of diminished immune surveillance, when the extracellular environment is more hospitable to tumor cell proliferation. Overall, surgery promotes the spread of tumor cells, the survival of circulating tumor cells by boosting their immune evasion, the trapping of tumor cells at the metastatic location, and the ability of tumor cells to invade and migrate to generate new metastatic foci. The micrometastatic disease may be indirectly helped by surgery, which can alter its environment.

Metastasis contributes significantly to cancer patients’ morbidity and mortality. Surgery, which is meant to be a curative option to remove and decrease tumor bulk, may paradoxically also enhance the formation of metastases, as shown by both experimental and clinical data. By targeting perioperative variables that promote metastasis capture and dissemination, the postoperative phase may provide a unique opportunity to eradicate any lingering cancer cells.

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No funding was supported.

Author contribution

S.S., V.S., and S.K.R.S.: devised the concept, performed the literature search, and drafted the letter.

Conflicts of interest disclosure

There are no conflicts of interest.

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Guarantor

This submission is a correspondence. No new study was performed. All authors accept full responsibility for the submitted letter.

Data availability statement

The correspondence is based exclusively on resources that are publicly available on the internet and duly cited in the ‘References’ section. No primary data were generated and reported in this manuscript. Therefore, data have not become available to any academic repository.