Cell-Free Filtrates (CFF) as Vectors of a Transmissible Pathologic Tissue Memory Code: A Hypothetical and Narrative Review

Abstract

Cellular memory is a controversial concept representing the ability of cells to “write and memorize” stressful experiences via epigenetic operators. The progressive course of chronic, non-communicable diseases such as type 2 diabetes mellitus, cancer, and arteriosclerosis, is likely driven through an abnormal epigenetic reprogramming, fostering the hypothesis of a cellular pathologic memory. Accordingly, cultured diabetic and cancer patient-derived cells recall behavioral traits as when in the donor’s organism irrespective to culture time and conditions. Here, we analyze the data of studies conducted by our group and led by a cascade of hypothesis, in which we aimed to validate the hypothetical existence and transmissibility of a cellular pathologic memory in diabetes, arteriosclerotic peripheral arterial disease, and cancer. These experiments were based on the administration to otherwise healthy animals of cell-free filtrates prepared from human pathologic tissue samples representative of each disease condition. The administration of each pathologic tissue homogenate consistently induced the faithful recapitulation of: (1) Diabetic archetypical changes in cutaneous arterioles and nerves. (2) Non-thrombotic arteriosclerotic thickening, collagenous arterial encroachment, aberrant angiogenesis, and vascular remodeling. (3) Pre-malignant and malignant epithelial and mesenchymal tumors in different organs; all evocative of the donor’s tissue histopathology and with no barriers for interspecies transmission. We hypothesize that homogenates contain pathologic tissue memory codes represented in soluble drivers that “infiltrate” host’s animal cells, and ultimately impose their phenotypic signatures. The identification and validation of the actors in behind may pave the way for future therapies.

New Trends in Pathology: From Cell Morphology to Molecular Medicine

“…Catching a transmissible pathologic memory code was the main goal of the hypothesis paper published by Berlanga-Acosta et al, who administered cell-free filtrates, belonging to human tissues affected by cancer, diabetes or arteriosclerosis tissues, to healthy animals [16]. The authors observed the onset of pathological features (i.e., nervous and cutaneous alterations typical of type 2 diabetes, vasal thickening peculiar of arteriosclerosis and pre-carcinogenic lesions in mesenchymal and epithelial tissues).…”

Carcinogenic effect of human tumor-derived cell-free filtrates in nude mice

“…After Bernard Peyrilhe inaugurated the investigative use of human cancer-derived fluids, the administration of filtered cell-free tumor homogenates to animals has translated into groundbreaking contributions to experimental pathology ( Elemento, 2021 ). We recently undertook the use of cell-free filtrates (CFFs) derived from fresh human pathologic tissue samples to examine the hypothesis that the “chemical codes” of non-communicable diseases are imprinted in target tissues, which could be extracted, passively transferred to healthy animals, and accordingly reproduce the histological hallmarks of the human donor ( Berlanga-Acosta et al, 2022a ). These experiments demonstrated that CFFs acted as vehicles for delivering the soluble signalers that imposed the phenotypes of pathologic donors in otherwise normal animals ( Berlanga-Acosta et al, 2021 ; Berlanga-Acosta et al, 2022b ).…”

Carcinogenic Effect of Human Tumors-Derived Cell Free-Filtrates in Nude Mice

“…After Bernard Peyrilhe inaugurated the investigative use of human cancer-derived fluids, the administration of filtered cellfree tumor homogenates to animals, has translated in groundbreaking contributions in experimental pathology [21]. We recently undertook the use of cells-free filtrates (CFFs) derived from fresh human pathologic tissue samples, to examine the hypothesis that the "chemical codes" of non-communicable diseases are imprinted in target tissues, that could be extracted, passively transferred to healthy animals, and accordingly reproduce the histological hallmarks of the human donor [22]. These experiments demonstrated that CFFs acted as a vehicle for delivering the soluble signalers that imposed the pathologic donors' phenotypes in otherwise normal animals [23,24].…”