**3. Antitumor immunity**

The development of the primary tumor and its eventual ability to spread to a distance will depend on a balance between the potential for metastatic growth of the tumor and the immunity of antitumor host defense factors. The body's main antimetastatic defense mechanism is the immune system, which is evident in the high frequency of malignant tumors that develop in immunosuppressed people or under immunosuppressive treatment [4, 10].

Helper T lymphocytes (Th) are the main intrinsic modulators of the immune system, regulating the two main pathways of specific defense: cellular and humoral, through the secretion of cytokines. The profile of cytokines secreted by Th lymphocytes polarizes the immune response towards a predominantly cytotoxic or cellular one (Th1) or towards the other end, fundamentally humoral (Th2). These responses are antagonistic. In surgical procedures, the balance is tilted towards increased Th2 production, which is detrimental to cellular immunity and, consequently, the ability of cytotoxic T lymphocytes (CD8+) to fight tumor cells that may have detached from the tumor or that were already present far from the tumor during the surgical procedure [11].

CD8+ T lymphocytes, mononuclear cells, dendritic cells, and especially natural killer (NK) cells are the components of immunity to which anti-metastatic action has been attributed. Cellular immunity at the expense of NK cells plays a fundamental role in tumor recurrence and survival [12]. NK cells are known to be the first line of defense against the development of primary tumors and cells with metastatic spread. They are cells with an immediate response, capable of spontaneously recognizing and destroying tumor cells, identifying the cells as their own or foreign, through the expression of the major histocompatibility complex type 1 (MHC-1). When a cell expresses MHC-1, it inhibits the action of NK cells; and when it is absent, as occurs in tumor cells, they release the content of their granules that destroy the tumor cell membrane [13]. The reduction of its activity can cause an increase in the development of tumors, both primary and facilitate distant dissemination [14]. Patients with low levels of NK cell activity preoperatively have a higher incidence of cancer-associated morbidity and mortality. In favor of the above, a better prognosis has been observed after tumor resection in patients with high levels of NK cell activity at the time of surgery [15]. After surgical damage, an inflammatory reaction occurs at the local level that produces the secretion of proinflammatory cytokines: tumor necrosis factor-alpha (TNF-α), interleukins IL-1b, IL-6, IL-12, IL-15, IL- 18, and interferon-gamma (IFN-γ). The primary objective of the inflammatory response that appears after any surgical intervention is to repair and heal damaged tissues. In response to the proinflammatory state, an anti-inflammatory state is then produced in order to restrict inflammation to the injured tissues. Anti-inflammatory mediators are interleukins IL-4, IL-6, IL-10, IL-11, IL-13, and transforming growth factor beta (TGF-β), as well as catecholamines, prostaglandin E2 (PGE2), glucocorticoids, alpha-melanocyte-stimulating hormone (α-MSH), interleukin-1 receptor antagonist (IL-1Ra), and soluble TNF receptors [3].

There is evidence that the inflammatory process is responsible for much of the immunosuppression that appears after surgery and that inflammation itself has a tumorigenic role [16].

Vasodilation that occurs during inflammation is primarily mediated by nitric oxide (NO) and prostaglandins (PGE2, prostacyclin), being a factor that facilitates the supply of soluble mediators and inflammatory cells to the damaged area. These lipid mediators are produced by arachidonic acid through the action of cyclooxygenase (COX) and are considered pro-angiogenic since they serve to heal damaged tissue through the neoformation of vessels, this effect favoring the development of micrometastases [3].

Tumors larger than 2 millimeters (mm) are dependent on the formation of new blood vessels to receive the oxygen supply necessary to continue growing; therefore, for a micrometastasis to develop, an angiogenic process is needed, which will invariably occur when tissue is damaged. It has been seen that overexpression of vascular endothelial growth factor (VEGF) in colorectal cancer is associated with increased invasiveness and metastatic potential of the tumor [17].
