Surgery, Circulating Tumor Cells, and the Spread of Cancer
Questions from the Clinic:
Does surgical intervention increase or otherwise influence the number of circulating tumor cells in cancer patients and does that impact outcomes? Are there are any perioperative procedures or treatments that alter the activity of cancers and development of circulating tumor cells?
I. Historical Context
To achieve control of most solid cancers, clinicians frequently remain dependent on surgical resection. Although excision of primary tumors can save and extend lives, accumulating evidence indicates that the removal process may promote the metastatic seeding of cancer cells.(1) The link between tumor removal and recurrence has been known for much of the 20th century, but the mechanisms underlying this relationship took decades to elucidate fully.(2) Over time, investigators have directed their attention to circulating tumor cells, or CTCs, which travel to sites of physical or chemical injury.(3) Surgically-induced trauma can trigger a multifaceted, inflammatory response that promotes the migration and proliferation of CTCs.(2) Across multiple studies, researchers have noted that CTC counts rise after surgery for breast, colorectal, gastric, hepatocellular, and lung cancers.(4,5,6,7,8) Because postoperative disease recurrence locally and possibly distantly has a high risk of morbidity and mortality and occurs in upwards of a third of patients, it is arguably one of the greatest unresolved problems in modern medicine.(9)
II. Circulating Tumor Cells - Mechanism of Action
Surgical stress activates the sympathetic nervous system and several classes of immune cells that create conditions favorable for cancer growth. Elevated levels of epinephrine and norepinephrine results in the activation of β-adrenoceptors, which are upregulated on tumor cells. Once active, β-adrenoceptors initiate a cascade of intracellular signaling that culminates in the transcription of factors linked with metastasis, like HIFs, MMPs, and VEGF.9 Structurally, in response to these signals, tumor cells form actin-rich protrusions known as invadopodia.(10) Concurrently, flow through lymphatic vessels draining tumors increases in response to epinephrine and norepinephrine. This increased flow facilitates the dissemination of tumor cells in vivo, which are morphologically contractile and highly invasive.(11) The complement system, active during inflammation, further promotes cancer growth by enhancing the “stemness” or stem cell similarity of cancer cells, promoting angiogenesis, and reducing anti-tumor immunity.(1)
III. Completed Studies on Perioperative Factors
In addition to these mechanisms, perioperative factors may also profoundly influence the development of metastatic cancers. As early as the 1980s, researchers have demonstrated that anesthetic agents modulate inflammation and immune cell expression in murine models.(12) Notably, these effects manifest similarly in humans, with inhaled and intravenous agents alike contributing to tumor recurrence. Across multiple studies, patients exposed to inhalational isoflurane had upregulated transcription factors (HIF1-α, HIF2-α, and TGF-β) that promote tumor cell survival and migration.(13,14) Additionally, isoflurane appears to impair natural killer (NK) cells, which ordinarily combat CTCs.(15) Alternative intravenous options, like ketamine and thiopental sodium, also significantly reduce NK cell activity and increase the likelihood of metastasis in lung cancers.(16) Propofol, in contrast, appears to exhibit anticancer properties by decreasing cytokine production while preserving NK functionality.(9) Within breast cancer cells, conjugates of propofol with DHA and propofol with EPA blocked migration, induced apoptosis, and inhibited cell adhesion.(17) These findings align with those collected from a subsequent study, where investigators noted a 5% improvement in overall survival at 5 years for patients exposed to propofol-based intravenous anesthesia versus those exposed to volatile anesthesia.(18)
In addition to propofol, anti-inflammatory agents can significantly mitigate the risk of cancer during the perioperative period. Aspirin, an antithrombotic agent, possesses antiplatelet properties. By reducing platelet formation, aspirin can dismantle the biological cloak that CTCs use to evade detection and destruction by the immune system.(19) In one study assessing aspirin’s anticancer properties, investigators noted a direct, statistically significant correlation between daily aspirin use after surgery and a reduced risk of metastasis in patients with colorectal cancer (P < 0.0001).(20) These findings corroborate the results from an observational study where researchers noted similar associations in aspirin-treated patients with esophageal, breast, gastric, or biliary cancer.(21) Currently, a minimum of 3 clinical trials are assessing the effects of antithrombotic medications on the long-term outcomes of patients undergoing surgery for breast and colon cancer.(22,23,24) Beyond aspirin, heparin and propranolol and Toradol also control cancer growth by inhibiting the formation of platelet-CTC complexes and by inhibiting thromboxane synthesis, respectively.(9)
IV. Doxycycline & Hydroxyprogesterone – Recent Research
Application of other agents in the perioperative period, like doxycycline and hydroxyprogesterone, may also improve survival outcomes for patients with breast cancer. First approved by the FDA in 1967, the broad-spectrum antibiotic doxycycline acts as a selective non-toxic inhibitor of mitochondrial biosynthesis. This mechanism makes doxycycline a promising treatment to target cancer stem cells found in distant metastases. At the conclusion of a clinical pilot study, researchers noted that patients treated with 200 mg of oral doxycycline daily for 2 weeks before operative treatment had reduced markers for CTC such as CD44 and ALDH1 expression in tumor tissue.(25) Additionally, other markers of cancer “stemness” like Oct4, Sox2, and Nanog were reduced by greater than 50% as assessed by mRNA levels and immunoblot analysis.(26) Similarly, administration of hydroxyprogesterone before surgery appeared to confer a significant survival benefit in patients with node-positive operable breast cancer. Mechanistically, progesterone attenuates the inflammatory response to surgery by upregulating genes that decrease oxidative stress.(27)
V. Conclusions & Future Directions
In recent years, CTCs have also become quantifiable, measurable entities, thanks to advances in liquid biopsy technologies. This scientific advance represents a tremendous leap forward for oncologists, who can use CTCs as biomarkers to monitor tumor progression as well as the efficacy of selected treatments.(28) Across multiple prospective studies, investigators have noted that CTCs over 5/7.5 ml blood in metastatic breast cancer was associated with reduced progression-free survival and overall survival.(29) Additionally, this same threshold appears relevant in advanced prostate cancer, where CTC count may be superior to the conventional analysis of serum protein markers.(30) That said, clinical guidelines have not yet incorporated CTC counts as a recommended data point to consider while treating patients. Although treatments for cancer are continually improving, there still exist instances where no alternative therapies are available to treat certain cancers after CTCs rise. Other factors limiting CTC applications are low detection levels for certain tumor types and during early-stage disease.(31)
Looking ahead, improvements in CTC quantification technology may allow for better characterization of CTCs themselves. Greater insights into the genomic landscapes of tumor diseases, in turn, may facilitate the development of new therapeutic strategies.(31) Because accumulating evidence supports the correlation between CTCs and poorer prognostic outcomes, oncologists, surgeons, and supporting clinicians should consider safe measures to mitigate their development in the perioperative period. Although no standardized protocol exists to date for the use of anesthetics in cancer surgery, clinicians may want to consider minimizing CTCs by administering agents that positively modulate the stress response (i.e., inflammation).(9) In doing so, clinicians can help promote superior survival outcomes for their patients.
Stay strong, keep smiling and be your own best doctor,
- Chuck
Charles J. Meakin MD, MHA, MS
Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.
1 Chen Z, Zhang P, Xu Y, et al. Surgical stress and cancer progression: the twisted tango. Mol Cancer. 2019;18(1):132..
2 Tohme S, Simmons RL, Tsung A. Surgery for cancer: a trigger for metastases. Cancer Res. 2017;77(7):1548-1552.
3 Murthy SM, Goldschmidt RA, Rao LN, et al. The influence of surgical trauma on experimental metastasis. Cancer. 1989;64(10):2035-2044.
4 Brown DC, Purushotham AD, Birnie GD, et al. Detection of intraoperative tumor-cell dissemination in patients with breast-cancer by use of reverse transcription and polymerase chain-reaction. Surgery. 1995;117:96-101.
5 Peach G, Kim C, Zacharakis E, et al. Prognostic significance of circulating tumor cells following surgical resection of colorectal cancers: a systematic review. Brit J Cancer. 2010;102:1327-1334.
6 Zhang Q, Shan F, Li Z, et al. A prospective study on the changes and clinical significance of pre-operative and post-operative circulating tumor cells in resectable gastric cancer. J Transl Med. 2018;16:171.
7 Ou HH, Huang Y, Xiang LY, et al. Circulating tumor cell phenotype indicates poor survival and recurrence after surgery for hepatocellular carcinoma. Dig Dis Sci. 2018;63:2273-2380.
8 Duan XC, Zhu YJ, Cui Y, et al. Circulating tumor cells in the pulmonary vein increase significantly after lobectomy: a prospective observational study. Thor Cancer. 2019;10:163-169.
9 Hiller JG, Perry NJ, Poulogiannis G, et al. Perioperative events influence cancer recurrence risk after surgery. Nat Rev Clin Oncol. 2018;15(4):205-218.
10 Creed SJ, Le CP, Hassan M, et al. β2-adrenoceptor signaling regulated invadopodia formation to enhance tumor cell invasion. Breast Cancer Res. 2015;17:145.
11 Le CP, Nowell CJ, Kim-Fuchs C, et al. Chronic stress in mice remodels lymph vasculature to promote tumor cell dissemination. Nat Commun. 2016;7:10634.
12 Shapiro J, Jersky J, Katzav S, et al. Anesthetic drugs accelerate the progression of postoperative metastases of mouse tumors. J Clin Inv. 1981;67:678-685.
13 Iwasaki M, Zhao H, Jaffer T, et al. Volatile anesthetics enhance the metastasis related cellular signaling including CXCR2 of ovarian cancer cells. Oncotarget. 2016;7(18):26042-26056.
14 Huitink JM, Heimerikxs M, Nieuwland M, et al. Volatile anesthetics modulate gene expression in breast and brain tumor cells. Anesth Analg. 2010;111(6):1411-1415.
15 Desmond F, McCormack J, Mulligan N, et al. Effect of anesthetic technique on immune cell infiltration in breast cancer: a follow-up pilot analysis of a prospective, randomized investigator-masked study. Anticancer Res. 2015;35:1311-1319.
16 Melamed R, Bar-Yosef S, Shakhar G, et al. Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures. Anesth Analg. 2003;97:1331-1339.
17 Siddiqui RA, Zerouga M, Wu M, et al. Anticancer properties of propofol-docosahexaenoate and propofol-eicosapentaenoate on breast cancer cells. Breast Cancer Res. 2005;7:R645-R654.
18 Wigmore TJ, Mohammed K, Jhanji S. Long-term survival for patients undergoing volatile versus IV anesthesia for cancer surgery. Anesthesiology. 2016;124:69-79.
19 Mikami J, Kurokawa Y, Takahashi T, et al. Antitumor effect of antiplatelet agents in gastric cancer cells: an in vivo and in vitro study. Gastric Cancer. 2016;19(3):817-826.
20 Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomized trials. Lancet Oncol. 2012;13(5):518-527.
21 Liu J-F, Jamieson GG, Wu T-C, et al. A preliminary study on the postoperative survival of patients given aspirin after resection for squamous cell carcinoma of the esophagus or adenocarcinoma of the cardia. Ann Surg Oncol. 2009;16(5):1397-1402.
22 Aspirin in preventing recurrence of cancer in patients with HER2 negative Stage II-III breast cancer after chemotherapy, surgery, and/or radiation therapy. https://clinicaltrials.gov/ct2/show/NCT02927249. Updated May 27, 2021. Accessed August 14, 2021.
23 A trial of aspirin on recurrence and survival in colon cancer patients (ASPIRIN). https://clinicaltrials.gov/ct2/show/NCT02301286. Updated February 7, 2020. Accessed August 14, 2021.
24 Adjuvant aspirin treatment for colon cancer patients. https://clinicaltrials.gov/ct2/show/NCT02467582. Updated October 5, 2020. Accessed August 14, 2021.
25 Scatena C, Roncella M, Di Paolo A, et al. Doxycycline, an inhibitor of mitochondrial biogenesis, effectively reduces cancer stem cells (CSCs) in early breast cancer patients: a clinical pilot study. Front Oncol. 2018;8:452.
26 Zhang L, Xu L, Zhang F, et al. Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer. Cell Cycle. 2017;16(8):737-745.
27 Chatterjee S, Chaubal R, Maitra A, et al. Pre-operative progesterone benefits operable breast cancer patients by modulating surgical stress. Breast Cancer Res Treat. 2018;170(2):431-438.
28 Dasgupta A, Lim AR, Ghajar CM. Circulating and disseminating tumor cells: harbingers or initiators of metastasis. Mol Oncol. 2017;11(1):40-61.
29 Pang S, Li H, Xu S, et al. Circulating tumor cells at baseline and late phase of treatment provide prognostic value in breast cancer. Sci Rep. 2021;11(1):13441.
30 Vogelzang NJ, Fizazi K, Burke JM, et al. Circulating tumor cells in a phase 3 study of docetaxel and prednisone with or without lenalidomide in metastatic castration-resistant prostate cancer. Eur Urol. 2017;71(2):168-171.
31 Riethdorf S, O’Flaherty LO, Hille C, et al. Clinical application of the CellSearch platform in cancer patients. Adv Drug Deliv Rev. 2018;125:102-121.