Surgical stress response and promotion of metastasis in colorectal cancer: a complex and heterogeneous process

Abstract

Surgery remains the curative treatment modality for colorectal cancer in all stages, including stage IV with resectable liver metastasis. There is emerging evidence that the stress response caused by surgery as well as other perioperative therapies such as anesthesia and analgesia may promote growth of pre-existing micro-metastasis or potentially initiate tumor dissemination. Therapeutically targeting the perioperative period may therefore reduce the effect that surgical treatments have in promoting metastases, for example by combining β-adrenergic receptor antagonists and cyclooxygenase-2 (COX-2) inhibitors in the perioperative setting. In this paper, we highlight some of the mechanisms that may underlie surgery-related metastatic development in colorectal cancer. These include direct tumor spillage at the time of surgery, suppression of the anti-tumor immune response, direct stimulatory effects on tumor cells, and activation of the coagulation system. We summarize in more detail results that support a role for catecholamines as major drivers of the pro-metastatic effect induced by the surgical stress response, predominantly through activation of β-adrenergic signaling. Additionally, we argue that an improved understanding of surgical stress-induced dissemination, and more specifically whether it impacts on the level and nature of heterogeneity within residual tumor cells, would contribute to the successful clinical targeting of this process. Finally, we provide a proof-of-concept demonstration that ex-vivo analyses of colorectal cancer patient-derived samples using RGB-labeling technology can provide important insights into the heterogeneous sensitivity of tumor cells to stress signals. This suggests that intra-tumor heterogeneity is likely to influence the efficacy of perioperative β-adrenergic receptor and COX-2 inhibition, and that ex-vivo characterization of heterogeneous stress response in tumor samples can synergize with other models to optimize perioperative treatments and further improve outcome in colorectal and other solid cancers.

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery

“…Although carcinogenesis and disease progression may differ between carcinomas of different origin, basic mechanisms seem to be universal to the early metastatic process. TSE and TSF promote PMN and metastasis formation through the interplay between CTC, the immune system, stromal cells, vascular leakiness and ECM‐remodeling, all creating the perfect microenvironment for incoming tumor cells …”

“…Surgical resection is the mainstay in the treatment of most solid cancers. Nonetheless, emerging evidence shows that the surgical trauma, anesthesia, analgesia and postoperative complications may promote dissemination by direct effects on tumor cells, microenvironment and immune system thereby increasing the risk of recurrence …”

Editorial: Therapy-induced metastasis

“…Surgical procedures that are implicated in the promotion of metastasis are addressed in reviews from Alieva et al [15] and Behrenbruch et al [16]. Using high-resolution intra-vital microscopy in a mouse glioblastoma model, Alieva et al demonstrated previously that even a minor surgical trauma, such as fine-needle biopsy, could induce tumour cell migration and proliferation that could be prevented by blocking macrophage recruitment to the site of injury through inhibition of chemokine (C-C motif) ligand 2 (CCL-2) [17].…”

Peritoneal contamination with ICG‐stained cervical secretion as surrogate for potential cervical cancer tumor cell dissemination: A proof‐of‐principle study for laparoscopic hysterectomy

“…Criticism of the LACC study is based on the lack of a standardized surgical technique including possible use of uterine manipulators and intracorporal colpotomy without vaginal cuff closure, which might represent the strongest factor for increased recurrence rates due to intraoperative tumor dissemination . We already know from different cancer entities such as colorectal or pancreatic cancer that intraoperative tumor dissemination by surgical procedures is associated with increased recurrence rates . Several authors actually promote surgical techniques for cervical cancer treatment which aim to prevent tumor spillage during surgery .…”

“…1,8,9 We already know from different cancer entities such as colorectal or pancreatic cancer that intraoperative tumor dissemination by surgical procedures is associated with increased recurrence rates. [11][12][13] Several authors actually promote surgical techniques for cervical cancer treatment which aim to prevent tumor spillage during surgery. 9,14,15 To our knowledge, studies analyzing the probability or mechanisms of intraoperative peritoneal tumor cell dissemination for cervical cancer are lacking.…”