The Interplay Between Tumour Surgery and Cancer Metastasis

The primary treatment option for the majority of malign tumors is surgery. However, growing experimental and clinical evidence demonstrates that surgery itself can accelerate metastasis development. Reasons for that are numerous:

Growing experimental and clinical evidence demonstrates that surgery itself can accelerate metastasis development. 

Tumor shedding

Damage to the patients’ tissues during surgery has been shown to result in the shedding of tumor cells into the blood and lymphatic circulation (1). It has been shown that the number of circulating tumour cells (CTC) increased during, or shortly after resection in both peripheral and portal blood circulation, which suggests that manipulation of the primary tumor can lead to dissemination of tumor cells  (2-4). The meta-analysis demonstrated that these CTCs have a high prognostic value of metastasis incidence, independently of already established criteria such as tumor staging (5).

Decreased antitumor immunity

Surgery is associated with a transient suppression of immunologic functions mediated by the release of many anti-inflammatory mediators. That leads to decreased activity of macrophages and natural killer (NK) cells, that would otherwise protect a patient against metastases development by eliminating circulating tumor cells.

Surgery leads to a decreased activity of macrophages and natural killer cells, that would otherwise protect the patient

Increased tumor cell adhesion

The acute inflammatory response to surgery favors the gluing of tumor cells in distant tissues. It is mediated by two main factors: increased secretion of pro-inflammatory cytokines and increased production of reactive oxygen species (6).

All this points out that the biggest challenge may not be the removal of the primary tumor, but the effective prevention of metastasis development. The hard question is how it can be done? Some of the suggestions (6) are: reduced tissue damage through the development of better surgical techniques, immunotherapy through perioperative administration of immunostimulatory mediators,  more aggressive inhibition of tumor growth by perioperative chemotherapy, blocking CTC adhesion by for example blocking integrin molecules.

The biggest challenge may not be the removal of the primary tumour, but the effective prevention of metastasis development. 

In summary, there is a lot of opportunities to reduce the surgically induced spread of metastases but they are underutilized and underinvestigated. van der Bij et al. (2009) nicely summarized  what is probably the main obstacle:

Unfortunately, since clinical research investigating the effects of surgical resection on local and systemic metastases development has limitations, this topic is still subject of debate and not yet generally accepted despite the overwhelming evidence from experimental studies. Clearly, omitting surgery […] in an objective randomized clinical trial is unacceptable, and as such, we can only rely on anecdotal clinical evidence to evaluate this phenomenon.

References

  1. https://doi.org/10.1097/00000658-200007000-00009
  2. https://doi.org/10.1016/j.ejso.2004.09.005
  3. http://doi.org/10.1097/00000658-200007000-00009
  4. https://doi.org/10.1038/nrclinonc.2016.128
  5. https://doi.org/10.1186/s12885-015-1218-9
  6. https://doi.org/10.1097/sla.0b013e3181a3ddbd

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