The neurobiology of cancer is not a new concept. For a long time, it was claimed that tumors were devoid of innervation, but in the nineteenth century, Young [1], through histological preparations of impregnation with methylene blue, managed to observe nerve fibers in the parenchyma of different tumor types, such as mammary carcinomas and small round cell sarcomas. At that time, the accepted belief was that the nerves found in neoplastic tissues were there due to their entrapment from their pre-existence in healthy tissue. The transformation of healthy tissue and the accelerated cellular proliferation of the malignant cells would cause the invasion of adjacent tissues and thus confine the nerves within the neoplastic tissue. This being the case, when nerves are deprived of their function and invaded by neoplastic cells, they would eventually atrophy and disappear. In 1933, Ryrie [2] explained different theories about the anatomical and physiological relationship of nerve fibers in a neoplasm. His work highlights the thought of the existence of nerve fibers in tumors, the possibility that these are newly formed, perineural invasion (PI), fibrosis after damage as a result of PI and neural regeneration similar to peripheral damage within the neoplastic tissue. However, he concluded that there is no reason to assume any trophic influence on malignant cells [2]. In 1949, Shapiro published the results of his research regarding the relationship between nerves and tumor cells, and their possible physiological role in mesotheliomas and carcinomas in the anterior chamber of the eye, transplanted in mice and rabbits, respectively. In his conclusion, he supports the suggestion that the variation in the growth rate of tumors may be due to vasomotor changes caused by the alteration in the innervation present in each tumor [3].

On the other hand, during the 1950s, some studies were conducted to show the relationship between psychosomatic problems and the development of the disease. The organism is considered as a whole, so psychosocial problems may be more associated with the cause than with the effect of the disease, which is why it is suggested that the personality structure could play a role in the pathogenesis of cancer in individuals predisposed [4]. Psychological therapy, until then, was little used as a palliative practice in cancer patients and when exploring the benefit of intensive deep psychotherapy, a significant reduction in the size of the tumors presented by the patients was reported, when recognizing and working on traumatic events of their past [5]. On the contrary, it has been seen that patients suffering from cancer and manifesting problems of depression, anxiety, chronic stress, or social isolation, have poor prognoses, which include an accelerated progression of the disease, higher rates of recurrences, and low response to treatments, compared to those patients who do not have these disorders [6,7]. In other studies, when examining the association of social stress with relapse and mortality rates in some hormone-sensitive or lifestyle-related tumors, these have been found to be increased mainly in patients with breast [6], colorectal, pancreatic [8], and gastric tumors [7], a fact that is currently being corroborated in experimental works in vivo [9,10].

Until now, the role of the emotional factors in the carcinogenesis process is not entirely clear, however, the balance seems to tilt towards active participation in the cancer initiation and progression [11,12].

Some authors support that cancer is a disease of cellular differentiation, communication and tissue organization [13,14], and the environmental factor is described as one of the most important elements in the progression stage. The emotional state, in many cases, depends on the environment and has the ability to generate important biological modifications which can cause the prolonged release of molecules that could stimulate the formation of a tumor due to the signals it transmits and the processes it activates [10]. In addition, modifications or interruptions in the interactions between the nervous system and tissues are likely to transform the microenvironment and create the appropriate conditions for tumor development [9].

Over the years, cancer research has taken a reductionist approach, neglecting the complex functioning of a complete organism with all its component parts. Until now, the cancer study model has excluded important mechanisms, such as cellular communication through gap junctions, stem cells, mechanical damage [13,15], dysbiosis [16,17], ion channels [18,19,20], and the neurobiology of the oncological process.

Several studies support that people who present different stress-generating situations, such as a hostile family environment, a compromised economic situation or conditions of neglect or isolation, present accelerated progression of the disease with an ineffective response to treatment [6,21]. On the other hand, in different studies in which patients, in addition to pharmacological treatment, receive group and/or individual emotional therapy, coupled with physical exercise, or another type of social support and in some cases nutritional control, it was possible to observe an evident improvement, obtaining favorable results with a better response to treatments, prolonging disease-free survival, and notably improving quality of life [22,23]. Similarly, it has been proposed that character and personality, which define how we face adversity, could predispose to the development of breast cancer in women [24]. Studies in animals have produced results that support the fact that type of behavior at an early age causes differences in the production of endogenous glucocorticoids associated with the variation in the natural function of the Hypothalamic Pituitary Adrenal (HPA) axis, causing oscillation in the function of the immune system and generating individuals potentially susceptible to specific processes of disease at the end of life [25]. Therefore, if personality and character can predispose to the appearance of diseases due to the variations it causes in the functioning of the immune system, generally causing a suppressive effect, this could be the basis of the individual differences in the disease stages.

In support of the concept that the nervous system could play a central role in the pathophysiology of cancer, there is evidence that in healthy tissues, nerves and some of their products regulate various mechanisms deeply involved in the carcinogenesis process, such as: control stem cell proliferation [26,27], angiogenesis [28], cell migration [29], cell translocation [30], cell differentiation [31], recruitment and activation of immune cells [32], and energy metabolism [33]. All of them are necessary mechanisms in proliferative physiological processes such as embryogenesis, healing or epimorphic regeneration. In addition, these normal physiological proliferative processes, are nerve-dependent. When nerves are absent, they alter, delay, or these processes simply do not occur [27,34].

In the case of angiogenesis, it is known that nerves and blood vessels are closely related in structure and organization, both during embryonic development as in response to damage, and both depend on bidirectional signals for self-regulation [35]. In various tumors, it has been possible to identify areas with intratumoral nerve fibers, located by immunohistochemistry [36,37,38,39]. These fibers are frequently found on the periphery of tumors, some in the stroma and others in a perivascular manner, however, some blood vessels are devoid of innervation, in our opinion this could cause failure in cellular communication between both elements. Consequently, the angiogenic process would be deregulated and this could partially explain the irregular formation of blood vessels and their heterogeneity within a tumor [40].

Research on the neurobiology of cancer is so far scant. However, today there is greater interest and acceptance due to the evidence that is now available. For instance, epidemiological studies report a correlation between neuroactive therapies (benzodiazepines, lithium, or tricyclic antidepressants) with a reduced risk of cancer [41]. There is also an inverse correlation between neurodegenerative diseases and cancer. A good example is the case of patients with Parkinson’s disease or Alzheimer’s disease, where a low risk of cancer was identified, both before and after diagnosis [42].

Cognitive damage is a frequent event in cancer patients, and in some cases, diffuse brain damage has been identified through imaging studies. It is not clear whether this damage can occur as an adverse effect of anti-cancer therapies or neurodegeneration due to oxidative damage, inflammation and/or age effect associated with the oncologic disease [43]. Another interesting finding is the one that has been seen in patients with spinal cord damage and prostate denervation, who have a lower incidence of prostate cancer [44].

Other studies in patients with breast cancer have reported that women who use beta-blockers incidentally for some cardiovascular disease, before and/or during the year of breast cancer diagnosis, show a reduction in progression and mortality or remain free of the disease for a longer period, compared to patients who did not undergo beta-blocker treatment [45,46,47]. It is relevant to highlight that the use of beta-blockers seems to be more efficient in triple-negative breast tumors, which represents an option to be studied as a therapeutic target for this subtype of breast tumor, which has a highly aggressive biological behavior and so far, and does not show fully efficient treatment options [47].

The parallel benefit of the use of beta-blockers has been observed in complementary treatments in patients with other types of cancer, such as melanoma [48], pancreatic [49] and lung cancer [50]. In addition, it has been experimentally observed that treatments with beta-blockers in conjunction with other therapies, such as chemotherapeutics [51], immunotherapies with αPD-1 [48], or metformin [52], experimentally prevent the tumor growth and its progression. On the contrary, the action of catecholamines, when using adrenergic agonists such as isoproterenol, increases the occurrence of metastases to distant tissues compared to control tissues [9].

The development of metastases, via the hematogenous and/or lymphatic pathways, has long been considered the most relevant mechanism in malignancy and the leading cause of mortality in cancer patients. More recently, the neural pathway of metastasis was described and called perineural invasion (PI). Perineural invasion is considered a strong factor indicative of malignancy and has been associated with the worst prognosis [53].

Infiltration of neural tissues has been observed in various types of tumors, such as pancreatic [54,55], squamous cell carcinomas [56], and colorectal carcinoma [57,58,59], among others. Although the mechanisms by which this phenomenon occurs are not entirely clear, in vitro studies have shown that nervous and tumor tissue can have mutual tropism and exert chemoattraction, since the nervous tissue releases signaling molecules that guide tumor cells towards them [60,61].