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“L’Equipe BiavaVITA365, che ho costituito, si compone di dottori selezionati e formati specificatamente sull’epigenetica, la biofisica e la rigenerazione cellulare senza trapianto di cellule staminali. L’Equipe BiavaVITA365 prosegue insieme a me le ricerche scientifiche e opera clinicamente sulla base di protocolli scientifici integrati in pazienti affetti da malattie oncologiche, malattie cronico-degenerative, come quelle neuro-degenerative, cardio-vascolari ed infiammatorie, oltre che nella psoriasi, nelle malattie auto-immuni e nella prevenzione.
L’Equipe BiavaVITA365 viene continuamente formata ed aggiornata sulla base delle ricerche scientifiche che proseguiamo insieme per dare prospettive sempre nuove alla medicina.”
Cit. Prof. Pier Mario Biava
Da destra a sinistra: Prof. Pier Mario Biava, Dott. Stefano Ciaurelli diretto dell’Equipe BiavaVITA365.
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Le principali ricerche del Prof. Biava
Una sintesi editoriale delle ricerche raccolte nella pagina Reprogram Cells: dagli studi sperimentali sui fattori di differenziazione embrionale alle applicazioni cliniche in oncologia, psoriasi, neurodegenerazione, senescenza cellulare e approcci sistemici alle malattie cronico-degenerative.
1988
The first Experiments were published on Cancer Letter in 1988
Based on the hypothesis that the development of cancer is actively inhibited during embryonic life, the effects on tumor growth of homogenates of different tissues (embryos, uteri at ninth day of pregnancy, non-pregnant uteri and normal liver) were investigated in syngeneic C57BL/6 female mice. Primary tumor growth and spontaneous pulmonary metastasis formation were completely suppressed in the group of mice treated with pregnant uteri homogenates. Embryos, non-pregnant uteri and normal liver homogenates were ineffective.
1997
Activation of anti-oncogene p53 produced by embryonic extracts in vitro tumor cells.
Results demonstrate that substances present in the embryo during cell differentiation are able to activate p53
2001
CELL PROLIFERATION CURVES OF DIFFERENT HUMAN TUMOR LINES AFTER IN VITRO TREATMENT WITH ZEBRAFISH EMBRYONIC EXTRCTS
Five tumor cell lines of different origin (glioblastoma, melanoma, kidney adenocarcinoma, breast carcinoma and lymphoblastic leukemia) were treated in vitro with the extracts from zebrafish embryos collected at four different developmental stages. All cell lines responded with a significant slowing of the proliferation when treated with the extracts taken during the stages of cell differentiation, while no slowing effect was observed when they were treated with the extract taken from a merely multiplicative stage. These results suggest that a complex network of molecular factors during embryo differentiation may help abnormally proliferating cells to normalize their cycle, and that the administration of embryonic cell differentiation factors may be a useful tool in cancer therapy. On the other hand, it is known that the stem cells can be differentiated into different types of cells in relationship to different kinds of embryonic microenvironment. Since this network of cell differentiation factors may normalize the altered expression of genes, we suggest it as a sort of physiological gene therapy.
2001
Xenopus laevis embryos share antigens with zebrafish embryos and with human malignant neoplasms.
Previous experiments have demonstrated that antigens present in Xenopus laevis embryos are shared with human malignant neoplasms. In fact it is known that antisera raised in rabbit against pellet and supernatant fractions of Xenopus laevis embryos react to different antigens present in human tumors. The aim of the the present study was to evaluate whether these antisera react also to different antigens contained in zebrafish embryos at different stages of cell differentiation. This was done with the agar-gel immunodiffusion method performed according to an already described protocol. The results that we obtained show that both antisera raised in against pellet and supernatant fractions of Xenopus laevis embryos react to antigens of zebrafish at different stages of cell differentiation.
2002
Cancer and cell differentiation: a model to explain malignancy:
Cell Proliferation is affected by factors that are found in embryos and in pregnant uteri. This factors are organized in a network wohse complexity should be unscattered to retain its full efficacy. This is particulary true for embryos whose complex of molecular factors represents a closed microenviroment that can normalize the behavior of abnormously growing cell populations via a regulatory process involving key-role proteins of cell cycle homeostasis.
2002
Mother-embryo cross-talk: the anti-cancer substances produced by mother and embryo during cell differentiation. A review of experimental data: J. Tumor Marker Oncology
During pregnancy, a close cross-talk between mother and developing embryo is formed, made of a complex network of circulating molecular factors. This cross-talk is necessary for the prevention of pregnancy-threatening events, including the establishment of abnormally proliferating cell clones which may damage the integrity of this cross-talk.
2002
Post-traslational modification of the retinoblastoma protein (pRb) induced by in vitro administration of Zebrafish embryonic extracts on human kidney adenocarcinoma cell line
Tumor cells share several key-role features with embryonic cells. Tumor development is reduced or even suppressed in embryos during early differentiation processes suggest that factors present in the developing embryo may effect tumor growth. Experiments carried out in our lab showed that treatment of several tumor cell lines with embryonic and/or pregnant uteri homogenates inhibits tumor growth both in vitro and in vivo.
2002
Embryonic differentiation factors with anticancer properties:preliminary clinical results in the therapy for advanced tumors
It is possible to activate the p53 onco-suppressor after treatment with embryonic extracts on different tumor cells. The evidence that embryonic factors of cell differentiation can be used as a physiological gene therapy of cancer constituted the objective basis to prepare a therapy to test in human cancer. As a result, different products containing specific embryonic differentiation factors were prepared.
2005
Treatment with stem cell differentiation stage factors of intermediate-advanced hepatocellular carcinoma: an open randomized clinical trial
There is no standard treatment for patients with advanced hepatocellular carcinoma (HCC). We developed a product containing stem cells differentiation stage factors (SCDSF) that inhibits tumor growth in vivo and in vitro. The aim of this open randomized study was to assess its efficacy in patients with HCC not suitable for resection, transplantation, ablation therapy, or arterial chemoembolization. A total of 179 consecutive patients were enrolled. We randomly assigned the patients to receive either SCDSF or only conservative treatment. Primary end points were tumor response and survival. Secondary end points were performance status and patient tolerance. Randomization was stopped at the second interim analysis (6 months) of the first 32 patients recruited when the inspection detected a significant difference in favor of treatment (p = 0.037). The responses to the therapy obtained in 154 additional patients confirmed previous results. Evaluation of survival showed a significant difference between the group of patients who responded to treatment versus the group with progression of disease (p < 0.001). Of the 23 treated patients with a performance status (PS) of 1, 19 changed to 0. The study indicated the efficacy of SCDSF treatment of the patients with intermediate-advanced HCC.
2006
Zebrafish embryo proteins induce apoptosis in human colon cancer cells
Previous studies have shown that proteins extracted from Zebrafish embryo share some cytostatic characteristics in cancer cells. Our study was conducted to ascertain the biological properties of this protein network. Cancer cell growth and apoptosis were studied in Caco2 cells treated with embryonic extracts. Cell proliferation was significantly inhibited in a dose-dependent manner. Cell-cycle analysis in treated cells revealed a marked accumulation in the G(2)/M phase preceding induction of apoptosis. Embryo proteins induced a significant reduction in FLIP levels, and increased caspase-3 and caspase-8 activity as well as the apoptotic rate. Increased phosphorylated pRb values were obtained in treated Caco2 cells: the modified balance in pRb phosphorylation was associated with an increase in E2F1 values and c-Myc over-expression. Our data support previous reports of an apoptotic enhancing effect displayed by embryo extracts, mainly through the pRb/E2F1 apoptotic pathway, which thus suggests that Zebrafish embryo proteins have complex anti-cancer properties.
2011
Reprogramming of normal and cancer stem cells. Curr. Phar. Biotechnol
Over the last decade there has been an exponential rise in our understanding of the biochemical mechanisms controlling cell proliferation and differentiation. While the four transcription factors Oct4, Sox2, Klf4 and cMyc have shown to be sufficient to induce pluripotency in fibroblasts, there has in addition been much research into the mechanisms and pathways of cell differentiation and the specific properties of stem cells, namely their plasticity and capacity for trans-differentiation.
2011
Cancer cell reprogramming: stem cell differentiation stage factors and an agent based model to optimize cancer treatment. Curr. Phar. Biotechnol.
The recent tumor research has lead scientists to recognize the central role played by cancer stem cells in sustaining malignancy and chemo-resistance. A model of cancer presented by one of us describes the mechanisms that give rise to the different kinds of cancer stem-like cells and the role of these cells in cancer diseases. The model implies a shift in the conceptualization of the disease from reductionism to complexity theory. By exploiting the link between the agent-based simulation technique and the theory of complexity, the medical view is here translated into a corresponding computational model.
2011
Embryonic morphogenetic field induces phenotypic reversion in cancer cells. Curr. Phar. Biotechnol.
Cancer cells introduced into developing embryos can be committed to a complete reversion of their malignant phenotype. It is unlikely that such effects could be ascribed to only few molecular components interacting according to a simple linear-dynamics model, and they claim against the somatic mutation theory of cancer. Some 50 years ago, Needham and Waddington speculated that cancer represents an escape from morphogenetic field like those which guide embryonic development. Indeed, disruption of the morphogenetic field of a tissue can promote the onset as well as the progression of cancer. On the other hand, placing tumor cells into a “normal” morphogenetic field – like that of an embryonic tissue – one can reverse malignant phenotype, “reprogramming” tumor into normal cells.
2011
Zebrafish stem cell differentiation stage factors suppress Bcl-xL release and enhance 5-Fu-mediated apoptosis in colon cancer cells.
Stem cell differentiation stage factors (SCDSF), taken from Zebrafish embryos during the stage in which totipotent stem cells are differentiating into pluripotent stem cells, have been shown to inhibit proliferation and induce apoptosis in colon tumors. In order to ascertain if these embryonic factors could synergistically/additively interact with 5-Fluorouracil (5-Fu), whole cell-count, flow-cytometry analysis and apoptotic parameters were recorded in human colon cancer cells (Caco2) treated with Zebrafish stem cell differentiation stage factors (SCDSF 3 µg/ml) in association or not with 5-Fu in the sub-pharmacological therapeutic range (0.01 mg/ml). Cell proliferation was significantly reduced by SCDSF, meanwhile SCDSF+5-Fu leads to an almost complete growth-inhibition. SCDSF produces a significant apoptotic effect, meanwhile the association with 5-FU leads to an enhanced additive apoptotic rate at both 24 and 72 hrs.
2013
The zebrafish embryo derivative affects cell viability of epidermal cells: a possible role in the treatment of psoriasis.
In patients affected by psoriasis, use of a topical formula containing a derivative of zebrafish embryos was associated with reduced skin inflammation and dermal turnover, as well as a generally better outcome. In an attempt to understand the molecular mechanisms lying beyond these findings, we investigated the anti-proliferative effects of the zebrafish embryos derivative by addressing the mitochondrial function (MTT assay) and cell nuclei distribution (Hoestch staining). In cell cultures stimulated with fetal calf serum (FCS) or epidermal growth factor (EGF), the zebrafish derivative significantly inhibited cell proliferation induced by either approach, although the effect was stronger in cells stimulated with FCS. These results suggest that the zebrafish embryos derivative may dampen increased cell proliferation; this observation may be relevant to cutaneous pathologies related to altered proliferative mechanisms, including psoriasis.
2013
Rediscovering Meaning
The present crisis of the Western countries involves not just the world of politics, finance, and the economy, but also the ecosystem balance, the world of the values on which the model of social organization and economic development is based. The crisis is therefore systemic, epoch-making, and overcoming it will require radical changes, above all in the way we think, in our scale of values, and therefore our culture. On the other hand, for decades the world—in particular the West—has been experiencing a cultural sea-change that is challenging many of the pillars of society that have stood for centuries. The young people of today and their use of technological social networks to develop non-profit initiatives for social change may create a more positive future while maintaining our human values.
2014
A systemic approach to cancer treatment: tumor cell reprogramming focused on endocrine-related cancers.
The term “cancer cell reprogramming” is used to define any kind of intervention aimed at transforming cancer cells into terminally differentiated cells. Using this approach, new technologies have been applied with different methods for a more systemic approach to cancer treatment. This review reports on advances of these technologies, including our personal contributions, mainly carried out on endocrine-related cancers. Some of the interventions, aimed at reverting cancer cells into a normal phenotype, are based on the evidence that tumor development is suppressed by the embryonic microenvironment. On the basis of this rationale, experiments have been conducted using stem cell differentiation stage factors (SCDSFs) taken at different stages of development of Zebrafish embryos, oocyte extracts, or naïve human umbilical cord matrix derived stem cells (UMDSCs).
2014
Changing the endocrine dependence of breast cancer: data and hypotheses.
Among the most common human cancers, often only breast and prostate cancers have advantage of hormone dependence. For a long time, this advantage permitted breast cancer to be efficaciously managed in the adjuvant and metastatic settings with low side effects by endocrine therapy. Unfortunately, soon or afterward hormone dependence is lost in most patients. In breast cancer, de novo or acquired hormone resistance is an hot issue and the focus of endless debate. Although a lack of oestrogen receptors (ERs) is considered to be the main reason for de novo hormone resistance, many studies have been conducted and many different mechanisms have been hypothesised to account for acquired hormone resistance.
2014
The role of neuroendocrine cells in prostate cancer: a comprehensive review of current literature and subsequent rationale to broaden and integrate current treatment modalities.
Neuroendocrine prostate carcinoma (NE-PCa) is a heterogeneous disease. Due to a high prevalence of NE (neuroendocrine) differentiation in patients who receive prolonged androgen deprivation treatment, the real incidence of NE-PCa remains unknown. Similarly, the biological steps from prostate carcinoma (PCa) toward NE differentiation are far less than definitive and, consequently, there is a lack of evidence to support any of the treatments as the “gold standard”.
2014
Human Stem Cell Exposure to Developmental Stage Zebrafish Extracts: a Novel Strategy for Tuning Stemness and Senescence Patterning
BACKGROUND: Zebrafish exhibits extraordinary ability for tissue regeneration. Despite growing investigations dissecting the molecular underpinning of such regenerative potential, little is known about the possibility to use the chemical inventory of the zebrafish embryo to modulate human stem cell dynamics.
METHODS: Extracts from zebrafish embryo were collected at different developmental stages, referred to as ZF1, ZF2, ZF3 (early stages), and ZF4, ZF5 (late stages). Human adipose-derived stem cells (hASCs), isolated from microfractured fat tissue obtained with a novel non-enzymatic method (Lipogems), were cultured in absence or presence of each developmental stage extract. Cell viability was assessed by MTT assay. Nuclear morphology was investigated by cell-permeable dye 4’,6-DAPI. Caspase-3 activity was assessed by ELISA. Gene transcription was monitored by real-time PCR.
RESULTS: Late developmental stage extracts decreased cell viability and elicited caspase-3 mediated apoptosis. This effect did not involve Bax or Bcl-2 transcription. Conversely, early developmental stage ZF1 did not affect cell viability or apoptosis, albeit increasing Bax/Bcl-2 mRNA ratio. ZF1 enhanced transcription of the stemness/pluripotency genes Oct-4, Sox-2 and c-Myc. ZF1 also induced the transcription of TERT, encoding the catalytic subunit of telomerase, as well as the gene expression of Bmi-1, a chromatin remodeler acting as a major telomerase-independent repressor of senescence. These transcriptional responses were restricted to the action of early stage factors, since they were not elicited by late developmental stage ZF5.
CONCLUSIONS: Exposure to early developmental stage zebrafish embryo extracts may enhance stem cell expression of multipotency and activate both telomerase-dependent and -independent antagonists of cell senescence. These outcomes may prove rewarding during prolonged expansion in culture, as it occurs in most cell therapy protocols.
2015
Getting an Insight into the Complexity of Major Chronic Inflammatory and Degenerative Diseases: A Potential New Systemic Approach to Their Treatment.
As the modern society is troubled by multi-factorial diseases, research has been conducted on complex realities including chronic inflammation, cancer, obesity, HIV infection, metabolic syndrome and its detrimental cardiovascular complications as well as depression and other brain disorders. Deterioration of crucial homeostatic mechanisms in such diseases invariably results in activation of inflammatory mediators, chronic inflammation, loss in immunological function, increased susceptibility to diseases, alteration of metabolism, decrease of energy production and neuro-cognitive decline. Regulation of genes expression by epigenetic code is the dominant mechanism for the transduction of environmental inputs, such as stress and inflammation to lasting physiological changes. Acute and chronic stress determines DNA methylation and histone modifications in brain regions which may contribute to neuro-degenerative disorders. Nuclear glucocorticoids receptor interacts with the epigenoma resulting in a cortisol resistance status associated with a deterioration of the metabolic and immune functions. Gonadal steroids receptors have a similar capacity to produce epigenomic reorganization of chromatine structure. Epigenomic-induced reduction in immune cells telomeres length has been observed in many degenerative diseases, including all types of cancer. The final result of these epigenetic alterations is a serious damage to the neuro-endocrine-immune-metabolic adaptive systems. In this study, we propose a treatment with stem cells differentiation stage factors taken from zebrafish embryos which are able to regulate the genes expression of normal and pathological stem cells in a different specific way.
2015
The PI3K-AKt-mTOR Pathway and New Tools to Prevent Acquired Hormone Resistance in Breast Cancer
Acquired hormone resistance is an old hurdle and still represents to be a constant challenge in oncology for the medical community. Most recently, mainly following the results of BOLERO-2 study, the activation of the PI3K-AKT-mTOR pathway is considered clinically relevant for tumor escape from hormone dependence in breast cancer. In the BOLERO-2 trial, a combination of everolimus, mTOR inhibitor, and exemestane significantly prolonged the median progression free survival (PFS) compared to exemestane alone in advanced breast cancer patients with acquired endocrine resistance. Therefore, the inhibitors of the PI3K-AKT-mTOR pathway are a new class of drugs in great expansion joined with great expectation. This review article focuses on this special issue and briefly reports on the results of clinical trials using PI3K-AKT-mTOR inhibitors. However, the emergence of resistance to this new class of drugs, evidenced by the basic research and the relatively less benefit shown in the clinical trials, has been emerging as a new undesirable complication. Therefore, the principal elucidated mechanisms of the resistance to the inhibitors of the PI3K-AKT-mTOR pathway and the related potential therapeutic strategies are described. A more general immunological approach to delay acquired hormone resistance has also been considered and commented upon.
2016
New Views in the Integrative Treatment of Oncologic Disease: Stem Cell Differentiation Stage Factors and Their Role in Tumor Cell Reprogramming
On the basis of the evidence that tumor development is suppressed by the embryonic microenvironment, some experiments using the factors taken from Zebrafish embryo at precise stages of cell differentiation were made. These experiments demonstrated a significant growth inhibition on different tumor cell lines in vitro. The observed mechanism of tumor growth inhibition is connected with the key-role cell cycle regulation molecules, such as p53 and pRb, which are modified by transcriptional or post-translational processes. Research on apoptosis and differentiation revealed that treatment with these factors induces caspase-3 with a p73 apoptotic-dependent pathway activation and a concurrent significant normalization of e-cadherin and beta-catenin ratio. Other experiments found a synergistic effect on the colon cancer proliferation curve after the concurrent treatment with these factors and 5-fluorouracil. Finally, a product prepared for human therapy demonstrated 19.8% regression and 16% stable disease in an open randomized clinical trial on intermediate-advanced hepatocellular carcinoma. The aims of this article is to recall in a synthetic way all the aforementioned researches to explain deeply the rationale of this approach of reprogramming cancer cells.
2016
Cancer: A Problem of Developmental Biology; Scientific Evidence for Reprogramming and Differentiation Therapy
Current medical literature acknowledges that embryonic micro-environment is able to suppress tumor development. Administering carcinogenic substances during organogenesis in fact leads to embryonic malformations, but not to offspring tumor growth. Once organogenesis has ended, administration of carcinogenic substances causes a rise in offspring tumor development. These data indicate that cancer can be considered a deviation in normal development, which can be regulated by factors of the embryonic microenvironment. Furthermore, it has been demonstrated that teratoma differentiates into normal tissues once it is implanted in the embryo. Recently, it has been shown that implanting a melanoma in Zebrafish embryo did not result in a tumor development; however, it did in the adult specimen. This demonstrates that cancer cells can differentiate into normal tissues when implanted in the embryo. In addition, it was demonstrated that other tumors can revert into a normal phenotype and/or differentiate into normal tissue when implanted in the embryo. These studies led some authors to define cancer as a problem of developmental biology and to predict the present concept of “cancer stem cells theory”. In this review, we record the most important researches about the reprogramming and differentiation treatments of cancer cells to better clarify how the substances taken from developing embryo or other biological substances can induce differentiation of malignant cells. Lastly, a model of cancer has been proposed here, conceived by one of us, which is consistent with the reality, as demonstrated by a great number of researches. This model integrates the theory of the “maturation arrest” of cancer cells as conceived by B. Pierce with the theory which describes cancer as a process of deterministic chaos determined by genetic and/or epigenetic alterations in differentiated cells, which leads a normal cell to become cancerous. All the researches here described demonstrated that cancer can be considered a problem of developmental biology and that one of the most important hallmarks of cancer is the loss of differentiation as already described by us in other articles.
2016
Immunotherapy and Hormone-therapy in Metastatic Breast Cancer: A Review and an Update
Historically, antiestrogen is the first targeted therapy used in breast cancer treatment. In fact, its rationale lies in the molecular pathways elucidated by basic research. In estrogen receptor (ER)-alpha positive metastatic breast cancer patients, hormone-therapy remains the first option of treatment. While tamoxifen concomitant with suppression of ovarian function with luteinizing hormone releasing hormone (LHRH) agonists is the standard first line treatment in premenopausal, third generation aromatase inhibitors (AIs) are the first line standard hormone therapy in postmenopausal. However, the development of acquired resistance during antiestrogen therapy continues to be a central clinical problem. This review provides an update on the antiestrogen action and report on immunological treatment of the advanced disease by some cytokines. Interleukin-2, interleukin-12 and interferons used alone or in combination demonstrated an anti-tumor action directly and/or through synergism with antiestrogens. A rationale for the addition of interferon-beta and interleukin-2 to antiestrogens is described. Furthermore, we summarize and interpret the clinical and laboratory data of a recent long-term hormone- immunotherapy study in metastatic endocrine dependent breast cancer patients. Prospective randomized trials are necessary to confirm some recent promising results based on an immunological approach in addition to antiestrogens to overcome or delay acquired hormone resistance.
2018
Tissue Regeneration without Stem Cell Transplantation: Self-Healing Potential from Ancestral Chemistry and Physical Energies
The human body constantly regenerates after damage due to the self-renewing and differentiating properties of its resident stem cells. To recover the damaged tissues and regenerate functional organs, scientific research in the field of regenerative medicine is firmly trying to understand the molecular mechanisms through which the regenerative potential of stem cells may be unfolded into a clinical application. The finding that some organisms are capable of regenerative processes and the study of conserved evolutionary patterns in tissue regeneration may lead to the identification of natural molecules of ancestral species capable to extend their regenerative potential to human tissues. Such a possibility has also been strongly suggested as a result of the use of physical energies, such as electromagnetic fields and mechanical vibrations in human adult stem cells. Results from scientific studies on stem cell modulation confirm the possibility to afford a chemical manipulation of stem cell fate in vitro and pave the way to the use of natural molecules, as well as electromagnetic fields and mechanical vibrations to target human stem cells in their niche inside the body, enhancing human natural ability for self-healing.
2019
Novel Diagnostic Biomarkers of Prostate Cancer: An Update
OBJECTIVE: In recent years, several biomarkers alternative to standard prostate specific antigen (PSA) for prostate cancer (PCa) diagnosis have become available. The aim of this systematic review is to assess the current knowledge about alternative serum and urinary biomarkers for the diagnosis of PCa. MATERIAL AND METHODS: A research was conducted in Medline, restricted to English language articles published between December 2014 and June 2018 with the aim to update previously published series on PCa biomarkers. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) criteria were used for selecting studies with the lowest risk of bias. RESULTS: Emerging role and actual controversies on serum and urine alternative biomarkers to standard PSA for PCa diagnosis, staging and prognosis assessment, such as prostate health index (PHI), PCA3, ConfirmMDx, Aberrant PSA glycosylation, MiPS, miRNAs are critically presented in the current review. CONCLUSION: Although the use of several biomarkers has been recommended or questioned by different international guidelines, larger prospective randomized studies are still necessary to validate their efficacy in PCa detection, discrimination, prognosis and treatment effectiveness. To date, only PHI and 4Kscore have shown clinical relevance for discriminating more aggressive PCa. Furthermore, a new grading classification based on molecular features relevant for PCa risk-stratification and tailoring treatment is still needed.
2019
Zebrafish embryo extract counteracts human stem cell senescence
Human adult stem cells hold promise for regenerative medicine. They are usually expanded for multiple passages in vitro to increase cell yield prior to transplantation. Unfortunately, prolonged culture leads to cell senescence, a major drawback from successful outcomes in cell therapy approaches. Here, we show that an extract from early Zebrafish embryo (ZF1) counteracted senescence progression in human adipose-derived stem cells (hASCs) along multiple culture passages (from the 5th to the 20th). Exposure to ZF1 strongly reduced the expression of senescence marker beta-galactosidase. Both stemness ( NANOG , OCT4 , and MYC ) and anti-senescence ( BMI1 , and telomerase reverse transcriptase – TERT ) related genes were overexpressed at specific experimental points, without recruitment of the cyclin-dependent kinase Inhibitor 2A ( CDKN2A , ali-as p16 ). Increased telomerase activity was associatt-ed with TERT overexpression. Both osteogenic and adipogenic abilities were enhanced. In conclusion, hASCs exposure to ZF1 is a feasible tool to counteract and reverse human stem cell senescence in long-term culturing conditions.
2019
Active Fraction from Embryo Fish Extracts Induces Reversion of the Malignant Invasive Phenotype in Breast Cancer through Down-regulation of TCTP and Modulation of E-cadherin/β-catenin Pathway
Some yet unidentified factors released by both oocyte and embryonic microenvironments demonstrated to be non-permissive for tumor development and display the remarkable ability to foster cell/tissue reprogramming, thus ultimately reversing the malignant phenotype. In the present study we observed how molecular factors extracted from Zebrafish embryos during specific developmental phases (20 somites) significantly antagonize proliferation of breast cancer cells, while reversing a number of prominent aspects of malignancy. Embryo extracts reduce cell proliferation, enhance apoptosis, and dramatically inhibit both invasiveness and migrating capabilities of cancer cells. Counteracting the invasive phenotype is a relevant issue in controlling tumor spreading and metastasis. Moreover, such effect is not limited to cancerous cells as embryo extracts were also effective in inhibiting migration and invasiveness displayed by normal breast cells undergoing epithelial–mesenchymal transition upon TGF-β1 stimulation. The reversion program involves the modulation of E-cadherin/β-catenin pathway, cytoskeleton remodeling with dramatic reduction in vinculin, as well as downregulation of TCTP and the concomitant increase in p53 levels. Our findings highlight that—contrary to the prevailing current “dogma”, which posits that neoplastic cells are irreversibly “committed”—the malignant phenotype can ultimately be “reversed”, at least partially, in response to environmental morphogenetic influences.
2019
Early Developmental Zebrafish Embryo Extract to Modulate Senescence in Multisource Human Mesenchymal Stem Cells
Stem cells undergo senescence both in vivo, contributing to the progressive decline in self-healing mechanisms, and in vitro during prolonged expansion. Here, we show that an early developmental zebrafish embryo extract (ZF1) could act as a modulator of senescence in human mesenchymal stem cells (hMSCs) isolated from both adult tissues, including adipose tissue (hASCs), bone marrow (hBM-MSCs), dental pulp (hDP-MSCs), and a perinatal tissue such as the Wharton’s Jelly (hWJ-MSCs). In all the investigated hMSCs, ZF1 decreased senescence-associated β-galactosidase (SA β-gal) activity and enhanced the transcription of TERT , encoding the catalytic telomerase core. In addition, it was associated, only in hASCs, with a transcriptional induction of BMI1 , a pleiotropic repressor of senescence. In hBM-MSCs, hDP-MSCs, and hWJ-MSCs, TERT over-expression was concomitant with a down-regulation of two repressors of TERT , TP53 ( p53 ), and CDKN1A ( p21 ). Furthermore, ZF1 increased the natural ability of hASCs to perform adipogenesis. These results indicate the chance of using ZF1 to modulate stem cell senescence in a source-related manner, to be potentially used as a tool to affect stem cell senescence in vitro. In addition, its anti-senescence action could also set the basis for future in vivo approaches promoting tissue rejuvenation bypassing stem cell transplantation.
2020
Stem cell growth and differentiation factors from Zebrafish embryo and their role as epigenetic regulators in hair regeneration: results after transdermal administration using cryopass laser treatment
Previous studies conducted over many years in our laboratories on zebrafish embryos, have enabled the identification of precise moments of stem cell differentiation in which a large number of genes switch on and off, a sign that the genome is undergoing substantial changes in gene expression. Factors of the early developmental stage of zebrafish embryo were able to regulate the stem cell expression of multipotency, enhancing the stemness genes Oct-4, Sox-2 and c-Myc. In addition to affecting stemness genes, which maintain stem cell identity, the occurrence of these factors in a primarily multiplicative stage also elicited the transcriptional activation of two major mechanisms capable of opposing stem cell senescence, including the gene expression of TERT, the catalytic subunit of telomerase, and the transcription of Bmi1, a Trithorax family of repressors which act as essential factors for the self-renewal of adult stem cells, and as key telomerase-independent repressors of cell aging1,2. On the contrary, molecules taken during differentiation events are able to reprogram pathological stem cells3.On the basis of studies on stem cell rejuvenation, a differentiation of many studies was made. In this study we present the clinical results of twenty men aged between 46 and 67 (average age 57) with androgenetic alopecia. They were treated with Stem Cell Growth and Differentiation Factors from Zebrafish embryo using cryopass-laser treatment for transdermal administration.The materials and methods used to prepare the Zebrafish extracts4 and the use of Cryopass Laser (5) have already been described. Results: All the patients demonstrated an initial regeneration of hair in the form of a soft fleece after the first treatment. This regeneration was consolidated with subsequent treatments and after about 10 treatments, the appearance of hair was comparable to adult and pigmented hair. At the six months check, the number of hairs in examined subjects was almost unchanged and there was a general improvement in the number and in the volume of the stem.The treatment did not have any adverse effect and was very well accepted by patients, who were satisfied with results obtained.
2020
The Use of Stem Cell Differentiation Stage Factors (SCDSFs) Taken from Zebrafish Embryos during Organogenesis and Their Role in Regulating the Gene Expression of Normal and Pathological (Stem) Cells
Studies conducted on Zebrafish embryos in our laboratory have allowed for the identification of precise moments of organogenesis in which a lot of genes are switched on and off, a sign that the genome is undergoing substantial changes in gene expression. Stem cell growth and differentiation stage-factors present in different moments of organogenesis have proven to have different specific functions in gene regulation. The substances present in the first stages of cell differentiation in Zebrafish embryos have demonstrated an ability to counteract the senescence of stem cells, reducing the expression of the beta-galactosidase marker, enhancing the genes Oct-4 , Sox-2 , c-Myc , TERT , and the transcription of Bmi-1, which act as key telomerase-independent repressors of cell aging. The molecules present in the intermediate to late stages of cell differentiation have proven to be able to reprogram pathological human cells, such as cancer cells and those of the basal layer of the epidermis in psoriasis, which present a higher multiplication rate than normal cells. The factors present in all the stages of cell differentiation are able to counteract neurodegeneration, and to regenerate tissues: It has been possible to regenerate hair follicles in many patients with androgenetic alopecia through transdermal administration of stem cell differentiation stage factors (SCDSFs) by means of cryopass-laser.
2022
Stem Cell Differentiation Stage Factors (SCDSFs) Taken from Zebrafish Embryo during Organogenesis and their Role as Epigenetics Regulators able to Reverse Neurosensory Hearing Loss
2024
Resolutive Treatment of Actinic Keratosis through Peptides Extracted from Zebrafish Conveyed Across Laser-assisted Transcutaneous Delivery (Cryopass Therapy)
Introduction: Actinic keratoses (AKs) are humans’ most common keratinocyte-derived precancerous lesions. They can be observed predominantly in fair-skinned individuals on sun-exposed surfaces. Another name for AKs is solar keratosis. The primary risk factor for AKs is cumulative UV exposure from sunlight and/or tanning salons. AKs may present on a patient as a few detectable lesions. Clinically, they present as scaly erythema lesions with various pigmentations. Surgery treatment is the only approach that can definitively resolve the illness. Method: The research aims to demonstrate the effectiveness of treating relapsing AKs through the use of factors present during organogenesis extracted from zebrafish caviar conveyed through a cryopass therapy device (cryolaser phoresis). These factors are peptides present during specific phases of organogenesis and have shown the capacity to reverse cancer and neurodegeneration processes through gene, transcriptional, translational, and post-translational regulation. Result: We found that 90% of patients responded. The percentage of responding patients was 100% among females and 80% among men. Conclusion: Our results confirm previous findings about the effectiveness of stem cell differentiation stage factors (SCDFs) in cancer and open new ways to integrate treatment.
2024
“IL RUOLO DEI FATTORI DI DIFFERENZIAZIONE DELLE CELLULE STAMINALI NEL TRATTAMENTO ONCOLOGICO: NUOVE PROSPETTIVE DI RICERCA”
I fattori di differenziazione giocano un ruolo cruciale nella regolazione della crescita e della specializzazione cellulare, intervenendo in processi biologici fondamentali come lo sviluppo embrionale e la rigenerazione tissutale. Nella biologia del cancro, la perdita di differenziazione cellulare è una caratteristica distintiva delle cellule tumorali, che adottano uno stato proliferativo indifferenziato e aggressivo. I fattori di differenziazione derivati da embrioni, in particolare quelli di Zebrafish, studiati per primi dal Dott. Pier Mario Biava, offrono un approccio innovativo per riprogrammare le cellule tumorali verso uno stato differenziato, riducendo la loro aggressività e sensibilizzandole alle terapie convenzionali. Obiettivi dello studio Questa revisione sistematica mira a sintetizzare e analizzare le evidenze precliniche e cliniche sul ruolo dei fattori di differenziazione derivati da embrioni, con un focus sugli studi del Prof. Pier Mario Biava sulla differenziazione cellulare senza trapianto di cellule staminali. L’obiettivo è valutare i meccanismi biologici, l’efficacia terapeutica e le prospettive future di questi agenti nel trattamento dei tumori. Metodologia La strategia di ricerca bibliografica è stata condotta nei database PubMed, Cochrane Library e Scopus utilizzando parole chiave come “factors of differentiation,” “stem cells”, “cancer cell reprogramming”, “CSCs”, “epigenetic regulator”, “Biava”, “tissue regeneration”, “zebrafish embryos,” “gene regulation”, “glioblastoma” e “oncology.” Risultati principali Gli studi preclinici dimostrano che i fattori di differenziazione riducono la proliferazione cellulare, promuovono la differenziazione e modulano il microambiente tumorale, con effetti significativi su cellule di glioblastoma e carcinoma mammario. Gli studi clinici pilota su pazienti con carcinoma epatocellulare e glioblastoma evidenziano miglioramenti nella stabilizzazione della malattia, qualità della vita e tollerabilità, specialmente in combinazione con terapie standard come la chemioterapia. Conclusioni I fattori di differenziazione derivati da embrioni, in particolare quelli studiati dal Prof. Pier Mario Biava, rappresentano un approccio innovativo e promettente nel campo dell’oncologia integrata. Questi agenti mostrano un potenziale significativo nel riprogrammare le cellule tumorali verso uno stato più differenziato, riducendone l’aggressività e migliorando la risposta alle terapie convenzionali. Queste evidenze sottolineano il potenziale terapeutico dei fattori di differenziazione come strumenti complementari nel trattamento dei tumori.
2024
Control of Cellular Differentiation Trajectories for Cancer Reversion
Cellular differentiation is controlled by intricate layers of gene regulation, involving the modulation of gene expression by various transcriptional regulators. Due to the complexity of gene regulation, identifying master regulators across the differentiation trajectory has been a longstanding challenge. To tackle this problem, a computational framework, single-cell Boolean network inference and control (BENEIN), is presented. Applying BENEIN to human large intestinal single-cell transcriptome data, MYB, HDAC2, and FOXA2 are identified as the master regulators whose inhibition induces enterocyte differentiation. It is found that simultaneous knockdown of these master regulators can revert colorectal cancer cells into normal-like enterocytes by synergistically inducing differentiation and suppressing malignancy, which is validated by in vitro and in vivo experiments.
2025
The function of Zebrafish embryo stem cell differentiation stage factors (SCDSFs) in organogenesis and their control on gene expression in normal and pathological (Stem) Cells
Our lab’s studies on zebrafish embryos have made it possible to pinpoint specific organogenesis times when a large number of genes are turned on and off, indicating that the genome is experiencing significant changes in gene expression. Stage-factors for stem cell development and differentiation that are present at various stages of organogenesis have been shown to have distinct roles in gene regulation. By decreasing the expression of the beta-galactosidase marker and increasing the transcription of Bmi-1, Oct-4, Sox-2, c-Myc, and TERT-all of which are important telomerase-independent repressors of cell aging-the compounds found in the early stages of cell differentiation in zebrafish embryos have shown promise in preventing the senescence of stem cells. It has been demonstrated that the chemicals found in the intermediate to late phases of cell differentiation can reprogram diseased human cells, including cancer cells and the basal layer of the epidermis in psoriasis, which exhibit a higher rate of multiplication than normal cells. All phases of cell differentiation contain elements that can prevent neurodegeneration and promote tissue regeneration: many patients with androgenetic alopecia have had their hair follicles restored by transdermal delivery of stem cell differentiation stage factors (SCDSFs) using cryopass-laser.