If you look at any collection of “common myths about cancer”, you will probably find reassurances about the idea that having cancer surgery might cause the cancer to spread to other parts of the body. I remember coming across this one some years ago being surprised – I’d never heard that one myself, but it was apparently a pretty widespread fear. You could imagine a situation where tumor cells are mechanically detached and could spread, but that’s actually less likely than it might seem, since not all of these cells can actually attach somewhere else and start growing again (although there are special situations where such disturbance, even to the level of taking a biopsy sample, is known to be risky).
What I didn’t know enough about, though, is an effect seen in breast cancer treatment. After surgery, the risk of being diagnosed with metastatic breast cancer peaks about 12 to 18 months later. It’s not a sure thing, fortunately, but it’s definitely a real effect, and one that would certainly lead to people thinking that the surgery had (somehow) spread the cancer around. That’s actually a pretty reasonable hypothesis, given the observations, so that particular “common myth” has something behind it. But how? The same effect is noted in patients who have undergone complete mastectomy, which doesn’t disturb the tumor tissue itself much (or at all). Alternatively, were these actively growing tumors that had spread before the surgery and were just too small to detect? Some have argued for this explanation, and it’s hard to disprove. There’s yet another plausible mechanism: these tumor cells might have had already spread before the surgery, but were somehow not growing, and something happened to change that. What is it about surgery that would allow them to start growing?
This new paper has what may well be the answer. Studying the effects of surgery in mouse models of metastatic cancer, it appears that the post-surgical wound healing response is the culprit. There appears to be an ongoing T-cell response that is holding down these potential metastatic tumors, but it’s disrupted by the inflammation response after surgery. Expressing GFP in murine mammary tumors and then injecting these into other (syngenic) mice caused a T-cell response to the GFP itself, and ultimately the tumors were rejected by the immune system. But surgically wounding these mice triggered an outgrowth of the tumors instead, probably through the actions of inflammatory monocytes (which differentiate into macrophages inside the tumor tissue).
What’s even more interesting is that these effects can be abrogated simply by treating the mice with NSAIDs to damp down the inflammation response. To avoid interactions between the tumor cells and the anti-inflammatory drugs, the procedure was to do the surgical wounding (with and without NSAID treatment with meloxicam) several days before the tumor cells were even injected, with time enough to clear the system out:
Notably, treatment with meloxicam did not appear to impede wound healing in these mice. Seven days after surgical wounding (4 days after the cessation of either meloxicam or saline treatment), D2A1-GFP cells were orthotopically injected contralateral to the wound site. Meloxicam treatment had no effect on tumor growth in the absence of surgical wounding (Fig. 4G, left). In contrast, in wounded groups, tumors in meloxicam-treated mice were significantly smaller than tumors in wounded mice treated with saline (P < 0.05; Fig. 4G, right). Surprisingly, tumors in wounded, meloxicam-treated mice were even smaller than tumors in unwounded, untreated mice.
Interestingly, there had been a retrospective study of breast cancer patients that suggested that treatment with NSAIDs seemed to reduce the metastatic events, but no one was sure if that was a direct mechanistic effect on pre-existing tumors, or on their possible activation. These results, though, suggest that it really is an activation mechanism, and that patients should be treated with NSAIDs in just this way.
We undertook to model a clinical phenomenon that occurs at low frequency and arises only with delayed kinetics in patients. We therefore used hundreds of mice to ensure that we had sufficient statistical power to draw firm conclusions. In considering these conclusions, we do not wish to suggest that tumor resection surgery be avoided because of the potentially negative side effects suggested previously by clinical data and demonstrated here experimentally. Instead, we argue that coupling surgery with short-term anti-inflammatory treatments may substantially improve patient outcomes by mitigating the systemic consequences of surgical breast cancer resection. Of critical importance, perioperative treatment with the anti-inflammatory drug meloxicam potently inhibited the impact of wounding on tumor growth. Furthermore, our study suggests that the treatment of breast cancer patients with anti-inflammatory agents during and after surgical resection of primary tumors may yield substantial benefits by reducing the incidence of early metastatic relapse.
There seems to be no reason for this not to immediately move into clinical practice, and I hope that this paper gets widely noticed. NSAID therapy is cheap and well-tolerated, and the risk/benefit ratio would seem to be about as good as it can get. So in general, untangling the relationships of the immune system with cancer is continuing to provide results – both in turning the immune response up and (in this case) turning it down. That process is most definitely going to continue. . .