Cancer surgery as a potential source of metastasis.!





Amr Al-Haidari, PhD
March 17, 2016





It is well known that colorectal cancer, CRC, remains a big global challenge, although the last decade has tremendously moved cancer research huge steps forward, but the number of death cases has not decreased that much. The growing trend of death cases has made CRC the third leading cause of cancer-related deaths worldwide. One of the most important reasons attributed to such aggressiveness and increase mortality rate is the ability of cancer to spread to distant organs in a complex process called metastasis. When cancer spreads, we loss control over such disease and patient’s survival in most cases is reduced.





Cancer surgery is implicated in cancer metastasis


Despite being surgery the most effective cancer therapy for the majority of primary tumors, it is still challenging to control cancer cells release during surgical removal of cancerous tissue and therefore spread of cancer to distant organ is more likely resulted from such intervention. Surgery almost always disrupts the tissue integrity including tumor blood network which leads to release cancer cells into blood stream or seeding cells in the chest or abdomen. Supporting this notion, a growing body of evidence has revealed that cancer surgery can increase risk of metastasis (1). Another groundbreaking study reported that inflammation caused by cancer surgery can create an environment that facilitates cancer cell adhesion and thereby enhance metastasis(2). Further analysis on clinical data examined the surgical treatment out comes of colon cancer patients concluded that surgical removal of colon cancer tissue improved the clinical course and survival rate of the patients. However, some patients had decreased survival simultaneously after surgery due to cancer spread. Interestingly, Studies have also shown that cancer surgery increases tumor cell adhesion 250% to blood vessels compared to cancer cells not exposed to surgical conditions(3). Experimental studies have demonstrated that increase tumor progression was tightly related to immune system suppression induced by surgical stress (4). Th1 cells and cytotoxic lymphocytes have shown to be impaired after surgery along with decrease numbers of NK cells. Moreover, increase Treg cells recruitment at the site of surgery has also been shown to be significant prognostic factor. With evidences become clear that cancer surgery could be risky, patients started to think seriously on what additional interventions could reduce the risk of cancer surgery-related metastasis.





Inflammation and cancer


To gain a better understanding of how cancer therapeutic preventive measurements can aid in better survival in patients after cancer surgery, we need to address clearly different mechanisms which increase risk of surgery-induced metastasis and the key players in such mechanisms. Cancer spread can initiate its journey through mutli-complex step starting with increasing cancer cell adhesion due to release cells during surgery. One of the most important gun-trigger metastasis bullet is inflammation at the site of the surgey. Inflammation create a favourable environment for cancer cells to adhere by meanings of increase cytokines and chemokines release, upregulation of adhesion molecules such as ICAM, VCAM, Beta integrins, E-cadherin, selectins, in addition to chemokine receptors (5). In this context, it is worth noting that the development of CXCR2 antagonist has revealed some super interesting findings in reducing adhesion of some tumors. These molecular targets are potential arena for developing cancer drugs to reduce metastasis and actually there are some now have been moved to clinical bench for testing.





Immune system alteration after cancer surgery


Another cancer-key mechanism of spread after surgery is the immune system alteration. Suppressing immune function as mentioned earlier contributes negatively in cancer progression. Immunomodulation of tumor environment can be summarized into three main stages; 1, Cancer cell elimination, where the immune system is able to fight the cancer following successful immune surveillance. 2, Balance state, where the immune system controls transformed cells but has not eliminated them. The third stage where the immune surveillance is unable to detect the tumor and or when tumor tolerated the immune system (6) , therefore cancer cells escaped and start the party. Patients usually presented after the third stage have in general poor prognosis especially if the cancer has been spread to distant organs. Recent findings showed promising move in immunotherapeutic approch of cancer where NK cells from the same patient are isolated and cultured in vitro to increase cell amount besides enhancing proliferation, and then re-injected again to the same patient. While immunotherapy has shed the light on possible modulation of cancer immunity, there is rapid development of some molecular targets on the other side of the therapeutic race and both will definitely make a major difference in improving overall survival of cancer patients after surgery.



Selected references


Zhao T, Xia WH, Zheng MQ, Lu CQ, Han X, Sun YJ. Surgical excision promotes tumor growth and metastasis by promoting expression of MMP-9 and VEGF in a breast cancer model. Exp Oncol. [Research Support, Non-U.S. Gov't]. 2008 Mar;30(1):60-4.


Klampfer L. Cytokines, inflammation and colon cancer. Curr Cancer Drug Targets. [Research Support, N.I.H., Extramural Review]. 2011 May;11(4):451-64.


Ten Kate M, Hofland LJ, van Grevenstein WM, van Koetsveld PV, Jeekel J, van Eijck CH. Influence of proinflammatory cytokines on the adhesion of human colon carcinoma cells to lung microvascular endothelium. Int J Cancer. 2004 Dec 20;112(6):943-50.


Myrthala Moreno-Smith,1 Susan K Lutgendorf et al. Impact of stress on cancer metastasis, Future Oncol. 2010 Dec; 6(12): 1863–1881. doi: 10.2217/fon.10.142


Konstantinos A. Paschos, , David Canovas et al. The role of cell adhesion molecules in the progression of colorectal cancer and the development of liver metastasis , doi:10.1016/j.cellsig.2009.01.006


Sathana Dushyanthen†, Paul A. Beavis et al. Relevance of tumor-infiltrating lymphocytes in breast cancer, BMC Medicine 201513:202, DOI: 10.1186/s12916-015-0431-3