The Immunologic Effects of Surgery: Spurring Tumor Growth


Richard Whelan, MD

Richard Whelan, MD, is director of surgical oncology and colon & rectal surgery at Mount Sinai St. Luke’s Roosevelt Hospital, in New York City. He was one of the first surgeons in New York to perform laparoscopic colectomy and helped develop hand-assisted minimally invasive surgical (MIS) techniques. Since 1996, he has directed a basic science and clinical research lab that has shown surgical procedures can cause temporary changes in a patient’s blood composition, changes that may promote the growth of cancer tumor deposits. General Surgery News spoke with Dr. Whelan after a presentation he gave at the 2016 Minimally Invasive Surgery Symposium.

Q. What inspired you to start looking at immunologic effects of surgery?

A. In 1996, laparoscopic surgery was becoming popular, but not in colorectal surgery because of fears about port-site tumors. We began by comparing laparoscopic with open surgery, looking at the effects on the physiology of the body. We also used tumor models in mice to look at port-site tumors and began to notice that major surgery affected the way tumors grew. We weren’t the first to notice this effect: There’s a body of literature that extends way earlier that shows surgical trauma somehow stimulates tumor growth. Since 1996, we focused on trying to find more information about these surgical trauma–related cancer effects.

Q. You’ve also studied this in humans?

A. We made the jump to human research in the 1990s, which confirmed what others had noted, namely, that surgery causes immunosuppression. If you do major surgery, you’ll get immunosuppressed for a brief time. It could be less than a week or a couple of days longer, but this seems to have an effect on how tumor cells behave for a while.

Q. Is there a difference between the effect of laparoscopic and open operations?

A. Ten years ago or so, we realized, in regard to blood compositional changes, open and laparoscopic surgery are very similar in regard to the way they affect tumor growth after surgery. We initially hoped that laparoscopy would be associated with a cancer survival benefit, but that just has not been borne out clinically. The laparoscopic and open methods probably are very similar in regard to the effects they have on proteins in the bloodstream.

Q. What are those effects?

A. When you do a major operation on somebody and you check the blood proteins that affect inflammation, you see changes that last anywhere from two to four days. Some of them last just 12 hours. These are real changes that you can detect if you measure cytokines and inflammatory markers, but they tend to disappear pretty quickly. This is the case with classic trauma markers such as interleukin-6 or C-reactive protein. They resolve pretty quickly. We stumbled on the fact that there’s another group of changes that last up to five weeks. We believe these more persistent changes are of more concern. If the proteins in question have the capacity to affect tumor growth, then they might stimulate the growth of residual tumor deposits or circulating tumor cells in the first month after the operation to remove the primary cancer. If you have an effect that lasts for five weeks, the chance of it stimulating tumor growth would be much greater. We’ve found the levels of vascular endothelial growth factor (VEGF), which is a very well-known protein, were elevated right after surgery and continued to rise. They peaked two weeks after surgery and were elevated for up to four weeks. That was a surprise because no one had ever shown that surgery had effects you could detect in the bloodstream that would persist that long.

Q. And there are changes that extend beyond VEGF?

A. We’ve found a total of 14 proteins that share this pattern of being elevated for three to five weeks after surgery. All of those proteins affect angiogenesis. Proteins that promote angiogenesis that are elevated for a long period of time after surgery might stimulate new blood vessel formation in existing tumor deposits, resulting in tumor growth. This could be a problem in patients who have a cancer removed but have some small, unknown metastases left behind.

Q. Do we see evidence of this outside of test tubes?

A. There are data in the literature about patients who show up with a liver cancer and a colon cancer at the same time. A number of studies show 25% to 35% of patients who first have surgery for a colon cancer will have marked growth in preexisting liver lesions or will develop new liver metastases in the three- to four-month interval before the liver resection is done [J Gastrointest Surg2008;12:1391-1398]. There’s also a study that looked at PET scans done before and after surgery in similar patients with simultaneous colon cancer and liver metastases. They found that those patients who had the colon tumor resected first, on repeat PET imaging a few months later, showed significantly increased FDG (18F-fluorodeoxyglucose) uptake [Surgery 2005;137:246-249]. The point is there is clinical evidence that when do you an operation like colectomy in someone who has liver metastases, it can stimulate the growth of those tumors.

Q. What’s the end goal for your research?

A. We want to prove to doctors and patients that we need to do some kind of anticancer treatment during that first month after and perhaps just before surgery. Most chemotherapy is started, at the earliest, one month after surgery. Most often in the United States, it’s six to eight weeks. We believe that we have shown that the first month may be a dangerous time period for cancer patients. Our lab is devoted to explaining and understanding the oncologic effects of surgery. We’re trying to find agents that are safe to take immediately before and after surgery that can slow tumor growth during this period when there may be stimuli to grow faster. The problem is that you cannot give something that will interfere with wound healing; thus, the drug must kill tumor cells but not inhibit healing.

Q. Have you found anything?

A. In the past, we gave immunomodulators perioperatively that showed some promise [Eur J Surg Oncol 2007;33:1169-1176]. Now, we’re doing a study wherein two antioxidants, one found in green tea and the other in milk thistle, are given to patients for a week before and three weeks after cancer surgery. We’ve checked these agents in animals and showed that they do inhibit growth, to some extent. Of note, they have also been shown not to inhibit wound healing in mice; therefore, they should be safe to take after surgery. This is an FDA-approved Phase I trial.

Q. Why do some changes after surgery last only a few days and others for weeks?

A. That’s a question we’re trying to answer this year. We think the source of all these proteins is the healing wounds. Angiogenesis is a critical part of the healing process and plays a key role in the tissue remodeling that occurs for over a month after surgery. We just presented a poster at the 2016 American Society of Colon and Rectal Surgeons annual meeting that showed that blood levels of eight angiogenesis-promoting proteins were significantly elevated after MIS colorectal resection during the month after surgery. Of note, the study also showed that wound levels of the same proteins were between six and 50 times higher than the blood levels. So, it looks like the extra protein is being made in the wounds and is then spilling into the bloodstream.

The wound is an area of intense growth, and the conditions that a wound needs to heal turn out to be the same conditions that a cancer needs to grow. If you look at a healing wound under a microscope and you look at a cancer, it’s hard to tell them apart. The difference is that the cells in a healing wound know to stop dividing when the tissue gap is filled. In a cancer, the cells keep growing. To put these findings in perspective, once the anesthesia-related changes and immediate effects of trauma have resolved two to five days after surgery, a second set of blood protein elevations occur that are related to wound healing. The wounds contain very high levels of these proteins. These blood protein changes render the blood proangiogenic. In patients with residual tumor deposits, these conditions may stimulate new blood vessel formation in the tumors that allow cancer growth. These findings, perhaps, explain why it now is standard practice not to remove the primary tumor in patients who have unresectable metastases, unless they are bleeding or obstructed. In the past, the primary tumor was routinely removed to reduce the tumor burden and then chemotherapy given. Results with chemotherapy alone are superior to those after primary resection followed by chemotherapy. The bottom line is that surgery is a double-edged sword, and there are times when it is best left in the scabbard.

Q. But you’ve said this effect of elevated blood proteins isn’t in all patients?

A. What we’ve reported is the mean or average levels for groups of patients. For all the proteins in question, the average late post-op levels are significantly elevated compared with mean pre-op blood levels. However, if you look at each patient, it turns out that maybe 25% to 40% of patients have a big increase, whereas other patients have modest increases or no elevation at all. We are currently in the process of trying to identify the characteristics of patients with big increases. If we can figure out who those patients are, we could perhaps modify the way in which we treat these patients.

Q. Based on the evidence now, what do you recommend surgeons do to minimize the negative effects of surgery?

A. The easy answer is that on our website we have a section on perioperative therapies. They’re holistic things, chemopreventive things: green tea and silibinin (milk thistle). Also cimetidine, an ulcer drug that is believed to suppress T cells that inhibit the immune response to tumors. There are data from four or five small clinical studies suggesting that perioperative cimetidine may improve cancer outcomes. We encourage our patients to consider taking one or several of these agents while they are waiting for surgery and for a month after surgery.

Q. What’s the take-home message for general surgeons about your research?

A. Surgery has many effects and most of them are good, but we’ve found something that may be a detrimental one. What this information does is gives me pause before I operate on a cancer patient. I want to make sure that there’s no option to give chemotherapy alone or before surgery. It’s important that we don’t rush into surgery without thinking of the possible ramifications. Also, we need to find safe and effective anticancer agents that can be given perioperatively.

Molecular Cross-Talk Promotes Tumor Growth.

Pancreatic tumor cells and neighboring normal cells engage in a two-way molecular conversation that helps drive malignant behavior in the cancer cells, according to new study results.

Working in cell lines from mice, researchers showed that pancreatic cancer cells that have cancer-causing mutations in the KRAS gene can coerce nearby healthy cells to release growth signals. These signals then activate a chain of events in the tumor cells that enhance their ability to survive and multiply.

The new findings, published May 5 in Cell, suggest that effective treatments for pancreatic cancer, which is notoriously difficult to treat, may need to target signaling pathways activated by adjacent stromal cells as well as those independently activated by the tumor cells, the study authors wrote.

Detecting Reciprocal Signaling

Pancreatic cancers and other solid cancers contain both tumor cells and normal connective tissue cells called stromal cells. Interactions between the two types of cells are known to play an important role in cancer growth and progression, but the molecular signals underlying these interactions are poorly understood.

To gain insights into these signals, a team led by Claus Jørgensen, Ph.D., of the Cancer Research UK Manchester Institute analyzed communication networks in a mouse pancreatic ductal adenocarcinoma (PDA) cell line and in pancreatic stromal cells from mice. PDA is the most common type of pancreatic cancer and one of the most deadly and difficult-to-treat human cancers.

The PDA cells used in this study contained a normal KRAS gene and a mutated form of the gene that the researchers could switch on or off. KRAS, which is mutated in more than 90 percent of pancreatic tumors and in many other cancers, plays a key role in driving the rapid and uncontrolled cell growth that are hallmarks of cancer.

For their analysis, the team monitored thousands of growth factors, receptors, and other proteins in the PDA cells alone, with and without the mutated form of KRAS; in stromal cells grown in the presence of factors that were secreted by the KRAS-mutant PDA cells; and in the two cell types grown together in laboratory dishes.

For the final experiment, the researchers tagged the proteins produced in the tumor cells with one label, and the proteins produced in the stromal cells with another label, explained Douglas Lauffenburger, Ph.D., of the Massachusetts Institute of Technology, a computational biologist and study coauthor. This technique allowed the researchers to monitor what was happening in the two cell types at the same time.

These experiments, along with computational analyses by Dr. Lauffenburger’s lab, yielded the first evidence that this type of molecular cross-talk, or reciprocal signaling, can expand the effects of cancer-causing gene mutations beyond those that occur in tumor cells alone and provided details on some of the key signaling molecules involved in these conversations.

In particular, the researchers found that PDA cells with mutated KRAS produced a growth signal known as sonic hedgehog, which induces the stromal cells to release growth factors, including Gas6 and IGF-1, that the cancer cells don’t produce on their own. These growth factors activated signaling pathways in the tumor cells that increased cell proliferation and protected the tumor cells from a type of controlled cell death called apoptosis.

An Intricate Web of Interactions

“We now know that tumors are a complex mix of genetically diverse cancer cells and multiple types of healthy cells, all communicating with each other via an intricate web of interactions,” Dr. Jørgensen said in a news release. “Untangling this web, and decoding individual signals, is vital to identifying which of the multitude of communications are most important for controlling tumor growth and spread.”

Because some pancreatic tumors contain even more stromal cells than they do cancer cells, understanding how cancer cells turn their healthy neighbors into allies is critically important, added lead author Christopher Tape, Ph.D., a research fellow at the Institute of Cancer Research, London.

Indeed, Dr. Lauffenburger said, “We can already imagine a combination of existing drugs that would be predicted to work much better [for treating pancreatic cancer] than drugs currently being used based on looking at tumor cells in isolation.”

One such combination he said, is drugs that inhibit the activity of the proteins AXL and MEK. Blocking AXL could disrupt an important pathway activated via reciprocal signaling from stromal cells, whereas blocking MEK would disrupt signaling that the tumor cells control on their own.

The next step, he said, will be to test such drug combinations in mouse models of pancreatic cancer. “If we can show that targeting these two pathways together is effective in mice, now you’ve got a toehold to think about whether there’s an indication for this kind of drug combination in human trials.”

If these results can be generalized to provide evidence for reciprocal signaling across different tumor types, “they could call into question the way that almost all cancer drug screens are performed, as well as many other conclusions that researchers draw from studying tumor cells in isolation,” said Daniel Gallahan, Ph.D., deputy director of NCI’sDivision of Cancer Biology.

“These results highlight the need to study cancer systematically in its ‘native’ environment, where tumor cells are able to communicate and respond to a variety of outside signals to enhance their growth,” Dr. Gallahan continued. “Through better understanding of the entire tumor ecosystem, there is potential for developing new therapeutic regimens designed to disrupt multiple processes, not just at the level of the tumor cell but also at other critical and potentially more targetable points.”