Surgical tumor resection triggering early metastatic relapse - the role of systemic inflammation.

Months or years after surgical primary tumor resection, cancer patients can relapse with secondary tumors arising in distant districts of the body (metastases).

Indeed, in parallel to primary tumor growth, subpopulations of cancer cells leave the primary tumor, migrate and disseminate at distant sites. These cells can remain in a quiescent state (meaning they do not proliferate until conditions become favorable); then, as the “brake” is released, they start proliferating, giving rise to metastases.

What is the trigger resuming proliferation of quiescent cells? Possibly, surgery itself may be the trigger, meaning that during the body response to the tissue damage induced by the surgery -the so-called “post-surgical wound healing response” -  factors previously constraining cells in a quiescent state are removed; like releasing a brake, cancer cells start proliferating.

Though clinical observation had previously suggested a link between surgery and early patient relapse, the proof and the underlying mechanism were still unclear, and only recently experimental evidence has been provided.

Indeed, when a sterile sponge is implanted in a mouse (mimicking surgical primary tumor resection and related tissue damage) previously injected with tumor cells at distant sites (mimicking quiescent disseminated tumor cells), enabling to discriminate between the inflammation induced by the surgical tumor resection and the presence of the primary tumor itself, provided evidence on the role of the systemic inflammation in the exit of disseminated cells from quiescence and the increased incidence of metastatic relapse short after surgery.

From the mechanistic point of view, surgery elicits systemic inflammation, which means higher inflammatory molecules in the bloodstream, and immune system cells -such as neutrophils and monocytes- moving from the bone marrow (where they originate from stem cells) to the bloodstream, ultimately boosting quiescent cells’ proliferation. This has been observed not only in the aforementioned experimental models, but in breast cancer patients after surgery as well.

Therefore, the administration of anti-inflammatory drugs to patients undergoing surgical tumor resection, reducing systemic inflammation, might represent a winning strategy to reduce the probability of post-surgery early metastatic relapse.

However, though many patients relapse short after surgery, some others may relapse with metastatic disease many years after surgical tumor resection, suggesting the existence of another different mechanism (forcedly not surgery-related) in the exit of cells from quiescence, and future studies will certainly unveil the process responsible for metastases formation.

Reference: The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Krall JA, Reinhardt F, Mercury OA, Pattabiraman DR, Brooks MW, Dougan M, Lambert AW, Bierie B, Ploegh HL, Dougan SK, Weinberg RA. Sci Transl Med. 2018.

Footnote. Though the approach described is interesting and well designed, enabling to uncouple primary tumor presence (and related factors) from the surgery-associated systemic inflammation (thus overcoming potential differences among different tumors in different animals -and patients- while highlighting the common aspects), personally some aspects still leave me considerable concern, such as the cells injected to mimic disseminated cells, which are not quiescent -hence not having the intrinsic features of quiescent cells-, but simply tumor cells whose proliferation is restricted by manipulation of the immune system (specifically, T cells). When systemic inflammation is induced, it overcomes dormancy imposed by T cells, but still, in my opinion, as it is not “faithfully mirroring” the actual condition generating metastatic dormancy, it slightly weakens the results on the role of systemic inflammation in the exit of cells form quiescence and following early patients’ relapse.