Spontaneous Regression of Cancer: Revealing Granulocytes and Oxidative Stress as the Crucial Double-edge Sword

Abstract

Background: It is commonly believed that cancer development is irreversible, organ-specific as well as systemic malignant disorder, often associated with harmful oxidative stress and inflammation. However, there are also well-documented cases of spontaneous cancer regression, the causative mechanisms of which are not understood. It is known that inflammation is a negative pathophysiological process that may support the development of cancer, but it is also believed that the immune system as well as oxidative stress play important roles in prevention of cancer development and defense against tumor progression. Hence, in animal models spontaneous regression of cancer could be mediated by rapid inflammatory response of granulocytes, acting against cancer mostly as innate immune response. In addition, the administration of granulocytes at the site of solid tumors can lead to tumor regression or can slow down tumor growth and extend the overall survival of animals. In both cases, similar to the radiotherapy, surgery and various chemotherapies, oxidative stress occurs generating lipid peroxidation product 4-hydroxynonenal (4-HNE). This "second messenger of free radicals" acts as growth regulating signaling molecule that exerts relatively selective cytotoxicity against cancer cells. Conclusions: We hypothesize that abundant inflammation and metabolic changes caused by cancer and oxidative stress producing of 4-HNE may be crucial mechanisms for spontaneous cancer regression.

Unexpected Transient Glioblastoma Regression in a Patient Previously Treated with Bacillus Calmette–Guérin Therapy: A Case Report and Immunomodulatory Effects Hypothesis

“…Indeed, surgical procedures (intended both as biopsy and resection of the primary tumor or metastases) may elicit immunologic surveillance through proinflammatory injuries leading up to complete regression of any residual macroscopic distant tumor [27]. This very rare phenomenon has been reported for a variety of tumor histologies, although not yet for gliomas [25,26,[28][29][30].…”

Lipid Peroxidation-Related Redox Signaling in Osteosarcoma

“…Redox reprogramming is among the hallmarks of cancer, and plays a crucial role in the initiation, development, and progression of cancer. Its roles in tumorigenesis and the onset of metastasis have been covered in recent reviews [22,33,34]. Below, redox reprograming in cancer in general and in particular in OS is discussed.…”

The 4-Hydroxynonenal–Protein Adducts and Their Biological Relevance: Are Some Proteins Preferred Targets?

“…4-HNE affects various cellular processes in a concentration-dependent manner, from proliferation and differentiation to autophagy and cell death such as apoptosis or ferroptosis [ 27 , 118 , 119 ]. Therefore, it is not surprising that 4-HNE not only plays an important role in carcinogenesis but also in the defense of normal cells against cancer [ 120 , 121 , 122 , 123 , 124 ]. Thus, it seems that the generation of 4-HNE and the way it acts are not merely accidental but rather targeted.…”