4. Angiogenesis in Adrenocortical Tumors
Adrenocortical tumors (ACT) are common adrenal tumors affecting 3% to 10% of the human population [
56]. The majority of ACT are benign non-functioning adrenocortical adenomas (ACA), while malignant ACC are rare with an incidence of 0.7 to 2 per million per year [
56]. ACC most often have a poor prognosis and are frequently already metastasized when first diagnosed. ACC pathogenesis is still largely unclear, which results in a lack of biomarkers available for diagnosis and in limited treatment options [
57,
58].
The status of the VEGF pathway in adrenocortical tumors has been already addressed in multiple studies ().
Table 1. VEGF pathway findings in adrenocortical tumors.
Patient Group Comparisons |
Results |
VEGF |
Patients with ACT vs. Healthy individuals |
↑ VEGF serum levels in patients with ACT [59,60] |
Aldosterone secreting ACA vs. Non-functioning ACA |
↑ VEGF tumor expression in aldosterone producing ACA [61] |
Cortisol secreting ACA vs. Aldosterone secreting ACA |
↑ VEGF serum levels patients with cortisol secreting ACA [60] |
ACC vs. Normal adrenal glands |
↑ VEGF expression in ACC [61,62] |
ACC vs. ACA |
↑ VEGF serum levels in ACC ↑ VEGF tumor expression in ACC [59,61,63,64] |
Patients with recurrent ACC vs. Patients with non-recurrent ACC |
↑ VEGF serum levels in recurrent ACC ↑ VEGF tumor expression in recurrent ACC [60,63] |
Localized ACC vs. Invasive ACC |
No difference in VEGF tumor expression [63] |
VEGF-R2 |
ACC vs. Normal adrenal glands |
↑ VEGF-R2 tumor expression in ACC [62] |
ACC vs. ACA |
↑ VEGF-R2 tumor expression in ACC [64] |
Patients with ACT were found to present higher VEGF serum levels as compared to healthy controls [
59,
60]. In addition, Kolomecki et al. demonstrated that VEGF serum levels were significantly higher in patients with non-functioning malignant tumors than in patients with non-functioning ACA. Noteworthy, VEGF serum levels in patients with ACC were shown to decrease after tumor surgical resection and increase in patients who experienced tumor recurrence [
59]. de Fraipont et al. found that cytosolic VEGF-A concentrations were higher in ACC when compared to ACA, although not being significantly different when localized and more invasive ACC were compared [
63]. Nevertheless, cytosolic VEGF-A concentrations were higher in recurrent as compared to non-recurrent ACC after primary tumor resection [
63].
Tumor VEGF expression was also found to be higher in ACC as compared to normal adrenal glands and ACA [
61,
62,
64]. VEGF receptor 2 tumor expression was also found to be higher in ACC when compared with ACA and normal adrenal glands [
62,
64].
Bernini et al., however, found that tumor VEGF expression was not directly related with vascular density, which was lower in ACC as compared to ACA and normal adrenal tissue. The fact that a higher VEGF expression was not shown to be associated with increased vascular density in ACC, was somehow unsurprising since a high vascular density already characterizes normal adrenal cortex tissue. What surprised researchers was that despite ACC lower vascular density, patients still had a very short survival time [
61].
Other studies reported that although no differences in vascular density were noticed when ACC, ACA and normal adrenal glands were compared, blood vessels perimeter and area were higher in ACC when compared to ACA [
65,
66]. In addition, endothelial cell proliferation was higher in ACC [
66].
On an opposed direction, another group reported vascular density to be higher in malignant ACT as compared to benign ACT [
67]. Another study observed that in their series VEGF expression was positively correlated with vessel density [
64]. Pereira et al. also reported ACC to present a higher vascular density, but only when compared to cortisol secreting ACA [
68]. This could, however, be derived from cortisol anti-angiogenic effects [
69]. There is additional evidence supporting that adrenocortical angiogenic status could be tightly related to the tumor’s hormonal functionality. Bernini et al. found that VEGF tumor expression was higher in aldosterone secreting ACA as compared to non-functioning ACA and normal adrenal glands [
61]. In addition, in another study patients with cortisol-secreting ACA were found to have higher circulating VEGF levels than patients with aldosterone secreting adenomas [
60].
The discovery of EG-VEGF, a steroidogenic organ specific VEGF, brought some enthusiasm to the scientific community as a potential explanation to the contradictory angiogenic patterns in ACTs as well as a potential target for ACC treatment. Heck et al. characterized the expression of EG-VEGF and its receptors [prokineticin receptor 1 (PKR1) and 2 (PKR2)] in a large number of ACC, ACA and normal adrenal glands. In this study, EG-VEGF and both receptors PKR1 and PKR2 were found to be present in the majority of ACT. Moreover, the nuclear protein expression of either EG-VEGF or PKR1 or both in ACC was reported to be associated with higher mortality, suggesting that these could be used as prognostic markers for overall patient survival [
53].
New prognostic and diagnostic markers are needed to improve ACC clinical practice. As described in this section, the usefulness of angiogenic factors for ACC diagnosis and/or prognosis was already investigated. From those, VEGF was the one with more consistent and replicable results, being increased in ACC when compared with ACA [
59,
61,
63,
64], in particular in the recurrent malignant tumors [
60,
63]. However, due to the rarity of ACC, the number of patients included in each study is small. So, in the future, to validate this result, multi-center studies are needed to increase the samples/participants’ number and to uniformize the methodological approach to analyze the VEGF tumors expression in ACT. Stratified analysis according to tumors functionality are needed since in previous studies, it showed to influence VEGF levels.