Stem cell therapy: A paradigm shift in breast cancer treatment

As per the latest Globocan statistics, the high prevalence rate of breast cancer in low- and middle-income countries has led to it becoming the most common cancer to be diagnosed, hence posing a major public health challenge. As per this data, more than 11.7% of the estimated new cancer cases in 2020 were due to breast cancer. A small but significant subpopulation of cells with self- renewing ability are present in the tumor stroma and have been given the nomenclature of cancer stem cells (CSCs). These cells display a high degree of plasticity owing to their ability to transition from the slowly cycling quiescent phase to the actively proliferating phenotype. This attribute of CSCs allows them to differentiate into various cell types having diverse functions. Breast CSCs have a pivotal role in development, metastasis, treatment resistance and relapse of breast cancers. This review focuses on the pathways regulating breast CSC maintenance and the current strategies that are being explored for directing the development of novel, targeted, therapeutic approaches for limiting and eradicating this aberrant stem cell population.     

Stem cell transplantation for metastatic breast cancer: analysis of tumor contamination

The purpose of this study was to determine the efficacy, engraftment kinetics, effect of bone marrow tumor contamination, and safety of high-dose therapy and granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood progenitor cell (PBPC) support for patients with responding metastatic breast cancer. Forty two patients underwent G-CSF (10 μg/kg) stimulated PBPC harvest. PBPC and bone marrow aspirates were analyzed by histologic and immunocytochemical methods for tumor contamination. Thirty-seven patients received high-dose therapy consisting of cyclophosphamide 6 g/m², thiotepa 500 mg/m², and carboplatin 800 mg/m² (CTCb) given as an infusion over 4 d followed by PBPC reinfusion and G-CSF (5 μg/kg) support. No transplant related deaths or grade 4 toxicity was recorded. CD34+ cells/kg infused was predictive of neutrophil and platelet recovery. With a median follow-up of 38 months, three year survival was 44% with relapse-free survival of 19%. Histological bone marrow involvement, found in 10 patients, was a negative prognostic factor and was associated with a median relapse-free survival of 3.5 months. Tumor contamination of PBPC by immunohistochemical staining was present in 22.5% of patients and found not to be correlated with decreased survival. G-CSF stimulated PBPC collection followed by a single course of high dose chemotherapy and stem cell infusion with G-CSF stimulated marrow recovery leads to rapid, reliable engraftment with low toxicity and promising outcome in women with responding metastatic breast cancer.     

Stem cell therapy for nerve injury

Peripheral nerve injury has remained a substantial clinical complication with no satisfactory treatment options.Despite the great development in the field ofmicrosurgery,some severe types of neural injuries cannot be treated without causing tension to the injured nerve.Thus current studies have focused on the new approaches for the treatment of peripheral nerve injuries.Stem cells with the ability to differentiate into a variety of cell types have brought a new perspective to this matter.In this review,we will discuss the use of three main sources of mesenchymal stem cells in the treatment of peripheral nerve injuries.     

Stem cell therapy for retinal diseases

In this review, we discuss about current knowledge about stem cell(SC) therapy in the treatment of retinal degeneration. Both human embryonic stem cell and induced pluripotent stem cell has been growth in culture for a long time, and started to be explored in the treatment of blinding conditions. The Food and Drug Administration, recently, has granted clinical trials using SC retinal therapy to treat complex disorders, as Stargardt’s dystrophy, and patients with geographic atrophy, providing good outcomes. This study ’s intent is to overview the critical regeneration of the subretinal anatomy through retinal pigment epithelium transplantation, with the goal of reestablish important pathways from the retina to the occipital cortex of the brain, as well as the differentiation from pluripotent quiescent SC to adult retina, and its relationship with a primary retinal injury, different techniques of transplantation, management of immune rejection and tumorigenicity, its potential application in improving patients’ vision, and, finally, approaching future directions and challenges for the treatment of several conditions.     

Stem cell therapy for ischemic heart disease

Recent experimental and clinical observations have suggested that cell transplantation could be of therapeutic value for the treatment of heart disease. This approach was based on the idea that transplanted donor cardiomyocytes would integrate with the host myocardium and thereby directly contribute to cardiac function. Surprisingly, the observation that non-cardiomyogenic cells could also improve cardiac function indicates that functional integration of donor cells might not be required to achieve a beneficial effect. More recently, several observations have suggested the presence of a greater than anticipated developmental repertoire in adult-derived stem cells, which, if further validated, would offer unprecedented opportunities for the restoration of cardiac function in diseased hearts. Here, we discuss current issues regarding the potential use of stem cell transplantation for the treatment of ischemic heart disease.     

Stem cell potential for type 1 diabetes therapy

Stem cells have been considered as a useful tool in Regenerative Medicine due to two main properties: high rate of self-renewal, and their potential to differentiate into all cell types present in the adult organism. Depending on their origin, these cells can be grouped into embryonic or adult stem cells. Embryonic stem cells are obtained from the inner cell mass of blastocyst, which appears during embryonic day 6 of human development. Adult stem cells are present within various tissues of the organism and are responsible for their turnover and repair. In this sense, these cells open new therapeutic possibilities to treat degenerative diseases such as type 1 diabetes. This pathology is caused by the autoimmune destruction of pancreatic β-cells, resulting in the lack of insulin production. Insulin injection, however, cannot mimic β-cell function, thus causing the development of important complications. The possibility of obtaining β-cell surrogates from either embryonic or adult stem cells to restore insulin secretion will be discussed in this review.     

Stem cell based therapy for skeletal muscle diseases

The use of stem cells to repair and replace damaged skeletal muscle cells in chronic, debilitating muscle diseases such as the muscular dystrophies holds great promise. Different stem cell populations, both of embryonic and adult origin display the potential to generate skeletal muscle cells and have been studied in animal models of muscular dystrophy. These include muscle derived satellite cells; bone marrow derived mesenchymal stem cells, muscle or bone marrow side population cells, circulating CD133+ cells and cells derived from blood vessel walls such as mesoangioblasts or pericytes. The design of effective stem cell based therapies requires a detailed understanding of the molecules and signaling pathways which determine myogenic lineage commitment and differentiation. We discuss the great strides that have been made in delineating these pathways and how a better understanding of muscle stem cell biology has the potential to lead to more effective stem cell based therapies for skeletal muscle regeneration for devastating muscle diseases.     

Multiplexed cell signaling analysis of human breast cancer applications for personalized therapy

Phosphoprotein driven cellular signaling events represent most of the new molecular targets for cancer treatment. Application of reverse-phase protein microarray technology for the study of ongoing signaling activity within breast tumor specimens holds great potential for elucidating and profiling signaling activity in real-time for patient-tailored therapy. Analysis of laser capture microdissection primary human breast tumors and metastatic lesions reveals pathway specific profiles and a new way to classify cancer based on functional signaling portraits. Moreover, the data demonstrate the requirement of laser capture microdissection for analysis and reveal the metastasis-specific changes that occur within a new microenvironment. Analysis of biopsy material from clinical trials for targeted therapeutics demonstrates the feasibility and utility of comprehensive signal pathway activation profiling for molecular analysis.     

Stem cells in normal breast development and breast cancer

Abstract.  The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem-cell self-renewal and differentiation. Furthermore, we propose a model in which transformation of stem cells, or early progenitor cells, results in carcinogenesis. A key event in this process is the deregulation of normal self-renewal in these cells. Transformed mammary stem or progenitor cells undergo aberrant differentiation processes that result in generation of the phenotypic heterogeneity found in human and rodent breast cancers. This phenotypic diversity is driven by a small subset of mammary tumour stem cells. We will discuss the important implications of this mammary tumour stem-cell model.     

Versican G3 domain modulates breast cancer cell apoptosis: a mechanism for breast cancer cell response to chemotherapy and EGFR therapy

Overexpression of EGFR and versican has been reported in association with breast cancers. Considered oncogenic, these molecules may be attractive therapeutic targets. Possessing anti-apoptotic and drug resistant properties, overexpression of these molecules is accompanied by selective sensitization to the process of apoptosis. In this study, we exogenously expressed a versican G3 construct in breast cancer cell lines and analyzed the effects of G3 on cell viability in fetal bovine serum free conditioned media and evaluated the effects of apoptotic agent C2-ceramide, and chemotherapeutic agents including Docetaxel, Doxorubicin, and Epirubicin. Versican G3 domain enhanced tumor cell resistance to apoptosis when cultured in serum free medium, Doxorubicin, or Epirubicin by up-regulating pERK and GSK-3β (S9P). However, it could be prevented by selective EGFR inhibitor AG 1478 and selective MEK inhibitor PD 98059. Both AG 1478 and PD 98059 enhanced expression of pSAPK/JNK, while selective JNK inhibitor SP 600125 enhanced expression of GSK-3β (S9P). Versican G3 promoted cell apoptosis induced by C2-ceramide or Docetaxel by enhancing expression of pSAPK/JNK and decreasing expression of GSK-3β (S9P), an observation blocked by AG 1478 or SP 6000125. Inhibition of endogenous versican expression by siRNA or reduction of versican G3's expression by linking G3 with 3'UTR prevented G3 modulated cell apoptosis. The dual roles of G3 in modulating breast cancer cell resistance to chemotherapeutic agents may in part explain a potential mechanism for breast cancer cell resistance to chemotherapy and EGFR therapy. The apoptotic effects of chemotherapeutics depend upon the activation and balance of down stream signals in the EGFR pathway. GSK-3β (S9P) appears to function as a key checkpoint in this balance of apoptosis and anti-apoptosis. Investigation and potential consideration of targeting GSK-3β (S9P) merits further study.     

Stem cell therapy independent of stemness

Mesenchymal stem cell (MSC) therapy is entering a new era shifting the focus from initial feasibility study to optimization of therapeutic efficacy. However, how MSC therapy facilitates tissue regeneration remains incompletely characterized. Consistent with the emerging notion that secretion of multiple growth factors/cytokines (trophic factors) by MSC provides the underlying tissue regenerative mechanism, the recent study by Bai et al demonstrated a critical therapeutic role of MSC-derived hepatocyte growth factor (HGF) in two animal models of multiple sclerosis (MS), which is a progressive autoimmune disorder caused by damage to the myelin sheath and loss of oligodendrocytes. Although current MS therapies are directed toward attenuation of the immune response, robust repair of myelin sheath likely requires a regenerative approach focusing on long-term replacement of the lost oligodendrocytes. This approach appears feasible because adult organs contain various populations of multipotent resident stem/progenitor cells that may be activated by MSC trophic factors as demonstrated by Bai et al This commentary highlights and discusses the major findings of their studies, emphasizing the anti-inflammatory function and trophic cross-talk mechanisms mediated by HGF and other MSC-derived trophic factors in sustaining the treatment benefits. Identification of multiple functionally synergistic trophic factors, such as HGF and vascular endothelial growth factor, can eventually lead to the development of efficacious cell-free therapeutic regimens targeting a broad spectrum of degenerative conditions.     

Stem cell and cellular therapy developments

Recent discoveries on human and non-human stem cells have prompted the development of several studies aimed at the translation of laboratory evidences into novel clinical procedures collectively known as ‘cellular therapy’.In this regard, a number of features specifically related to the clinical setting require stringent evaluation, including, but not limited to: ethical appropriateness; donor and recipient informed consent; autologous versus allogeneic use; media and devices for cell collection, processing, characterization, storage and distribution; donor and recipient adverse events registration and management; risk-to-benefit and cost analysis; outcome analysis; production sites accreditation and management; regulatory oversight.This article describes recent national and international developments related to the distribution of cells and tissues for clinical use. Moreover, an example is reported of the implementation of a cellular therapy production site compliant with good manufacturing practices (GMPs) in a large European University hospital.     

Stem cell therapy for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive impairment. It is caused by synaptic failure and excessive accumulation of misfolded proteins. To date, almost all advanced clinical trials on specific AD-related pathways have failed mostly due to a large number of neurons lost in the brain of patients with AD. Also, currently available drug candidates intervene too late. Stem cells have improved characteristics of self-renewal, proliferation, differentiation, and recombination with the advent of stem cell technology and the transformation of these cells into different types of central nervous system neurons and glial cells. Stem cell treatment has been successful in AD animal models. Recent preclinical studies on stem cell therapy for AD have proved to be promising. Cell replacement therapies, such as human embryonic stem cells or induced pluripotent stem cell–derived neural cells, have the potential to treat patients with AD, and human clinical trials are ongoing in this regard. However, many steps still need to be taken before stem cell therapy becomes a clinically feasible treatment for human AD and related diseases. This paper reviews the pathophysiology of AD and the application prospects of related stem cells based on cell type.     

Strategies for breast cancer therapy with antiestrogens

Current clinical research is focused upon the application of adjuvant therapy for the treatment of breast cancer. Combination chemotherapy is the most successful adjuvant therapy for premenopausal patients whereas the antiestrogen tamoxifen (1 or 2 yr) is successful in postmenopausal disease. We have developed a unifying strategy for the treatment of breast cancer. The thesis is based upon the application of continuous adjuvant therapy with tamoxifen in a low estrogen environment. Chemotherapy causes a chemical castration in premenopausal patients. In contrast, tamoxifen causes an increase in steroidogenesis. A combination of both approaches will work against each other until ovarian failure occurs. Patients should be checked for castration to provide a low estrogen environment in which tamoxifen, a competitive antagonist of estrogen action, can effectively work. Laboratory evidence using carcinogen-induced rat mammary tumor models demonstrates the efficacy of long-term therapy. Studies with the human breast cell line MCF-7 grown in athymic mice show that tamoxifen is a tumoristatic agent so that once the therapy is stopped, tumors can be regrown by estrogen administration. Patients should receive continuous tamoxifen therapy to prevent the growth-stimulating effects of adrenal steroids, environmental and phyto-estrogens.