In work done by our group at the University of Pittsburgh, we tested the effect of stem cells on cancer cells that have been separated into two groups: fast-growing cells or dormant cancer cells. This better simulates the situation that we see in breast cancer patients in which there may be some cancer cells in other areas of the breast that are dormant.
Our studies showed that the dormant cancer cells are not activated to grow by the stem cells. This leads to the next question that we need answer about this therapy: When is it safe to use this therapy?
Given the possibility that stem cells could stimulate the growth of cancer cells, these treatments may be best used in patients who are clinically free of the cancer. Therefore, an important question to answer is about the timing of this treatment relative to the breast cancer surgery.
How long must we wait before administering this therapy to confirm that patients are free of disease? This can only be answered through careful clinical studies in a large number of patients who are followed over years.
Another concern is whether this therapy will interfere with breast cancer screenings. Any surgery to the breast will cause changes on mammography. It is very important for patients to tell mammographers about any procedures they have had so the radiologist can best interpret the results. There has been concern that injecting fat into the breast can result in changes that look dangerous in mammogram results because the fat may produce scaring and small calcifications in the breast.
This could lead to a high rate of biopsies that are not needed. However, a study conducted by our research group at the University of Pittsburgh demonstrates that the changes are no more severe than those we see after breast reduction, a commonly performed breast operation. Background Adipose tissue is the key component of soft tissues throughout the body that protect underlying structures and impart a normal appearance.
Adipose-Derived Stem Cells ASCs and Fat Grafting Human adipose-derived stem cells, first termed preadipocytes, were isolated nearly 40 years ago, though their multi-lineage potential was discovered only 10 years ago by Zuk and colleagues [ 2 ]. Open in a separate window.
Conclusions The use of autologous fat for correction of soft tissue defects has been utilized for more than a century. References 1. Tissue engineering with adipose-derived stem cells ADSCs : current and future applications. J Plast Reconstr Aesthet Surg. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. Cell-assisted lipotransfer: supportive use of human adipose-derived cells for soft tissue augmentation with lipoinjection.
Tissue Eng. Zuk PA. The adipose-derived stem cell: looking back and looking ahead. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends Biotechnol. Coleman SR. Structural fat grafting: more than a permanent filler. Plast Reconstr Surg. Aesthet Plastic Surgery. Discussion 56—7. Novel strategy for soft tissue augmentation based on transplantation of fragmented omentum and preadipocytes.
Adipose-derived stem and progenitor cells as fillers in plastic and reconstructive surgery. Improvement of the survival of human autologous fat transplantation by using VEGF-transfected adipose-derived stem cells. Supplementation of fat grafts with adipose-derived regenerative cells improves long-term graft retention. Ann Plastic Surg. Hypoxia-enhanced wound-healing function of adipose-derived stem cells: increase in stem cell proliferation and up-regulation of VEGF and bFGF.
Adipose stromal cells stimulate angiogenesis via promoting progenitor cell differentiation, secretion of angiogenic factors, and enhancing vessel maturation. Prolonged hypoxic culture and trypsinization increase the pro-angiogenic potential of human adipose tissue-derived stem cells.
Fat grafting to the breast revisited: safety and efficacy. Discussion — Cell-assisted lipotransfer for facial lipoatrophy: efficacy of clinical use of adipose-derived stem cells. However, more challenges emerge related to CAL including lack of a standardized surgical procedure, the controversy in the effectiveness of CAL, and the potential oncogenic risk of ADSCs in cancer patients. In this review, we summarized the latest research and intended to give an outline involving the biological characteristics of ADSCs as well as the preclinical and clinical application of ADSCs.
Fat grafting is widely used in plastic surgery for various diseases in recent decades, due to its advantages of biocompatible, easy access, cost-effective, less complications, and less damage to the donor sites [ 1 ]. In , Pittenger et al. Since then, cell therapy based on MSCs has developed and found an important role in the field of tissue engineering and regeneration medicine [ 6 ].
Zuk et al. ADSCs are demonstrated to have similar self-renewal, unlimited proliferation capacity, and pro-angiogenic capacity and can increase the concentration of pro-angiogenic factors, promote epithelial cell differentiation and neovascularization, and ultimately improve fat grafts survival and plastic effects [ 7 , 8 , 9 , 10 ].
ADSCs can also regulate local and systemic biological responses through both cell-to-cell communication and paracrine manner, including regulating immune responses, inhibiting apoptosis, promoting angiogenesis, mediating inflammatory responses, and matrix remodeling [ 11 , 12 , 13 ].
Due to these practical advantages, ADSC-based cell therapy has been widely applied for wound healing [ 14 , 15 , 16 ], soft tissue regeneration [ 17 , 18 ], and bone generation [ 19 ]. Thus, surgeons mixed an additional percentage of isolated and in vitro cultured ADSCs into lipoaspirate to obtain a novel fat graft, which was called cell-assisted lipotransfer CAL [ 21 ]. Both preclinical and clinical studies suggested that ADSC-based CAL could improve the survival of fat grafts and has been well used especially in breast augmentation and facial lipoatrophy [ 22 ].
Briefly, SVF is a mixture of cell populations that derives from lipoaspirate component by removing mature adipocytes after centrifugation.
SVF also contains certain percentage of macrophages, smooth muscle cells, lymphocytes, pericytes, and fibroblasts [ 23 ], which provides an abundantly cellular and molecular microenvironment for regulating ADSCs under clinical conditions. SVF technology is also widely used in clinical trials for wound healing, joint conditions, and urogenital and cardiovascular diseases [ 26 ], exhibiting pro-angiogenesis and neovascularization effect. Nevertheless, the relatively low number of published clinical studies, lack of standard protocol, and financial loss hinder the application of ADSC- or SVF-based cell therapy in clinical work.
Breast cancer patients are a special population different from breast augmentation and trauma patients. Although the safety of fat injection for breast reconstruction has been broadly confirmed by a large number of clinical trials [ 27 ], in vitro and in vivo studies in animal models have found that both adipocytes and ADSCs can affect the breast cancer microenvironment and promote breast cancer growth and metastasis [ 28 , 29 , 30 , 31 , 32 ].
In recent years, preclinical studies and clinical trials have been made to explore the safety and effectiveness of ADSCs in breast reconstruction and obtained some encouraging results. A meta-analysis by Laloze et al. However, large cohorts and longer follow-up are needed to affirm the safety of CAL technology in patients with malignancy.
This review aims to provide a brief review on both the clinical and molecular evidences on the role of ADSCs in breast cancer and potential application of ADSC-based CAL in breast reconstruction after oncology surgery.
ADSCs mostly distribute in perivascular niche [ 34 ]. Compared with bone marrow, ADSCs yield from fat tissue liposuction is fold greater with a much less invasive manner [ 20 ]. Actually, the exact phenotype of ADSCs remains unclarified because surface biomarkers differ depending on donor cites and culture passages in vivo and in vitro [ 23 ].
CD34 is limited to ADSCs freshly isolated or cultured within 8—12 passages in vitro, indicating that CD34 plays as a niche-specific marker of immature cells or precursors [ 35 , 36 ]. Suga et al. Nevertheless, when CD34 turned negative after long-time expansion in vitro 25 passages , ADSCs still showed strong proliferative ability and multi-differentiation potential [ 37 , 39 ]. ADSCs represent a group of heterogeneous cells exhibiting similar pluripotential ability to MSCs in vitro and in vivo and can differentiate into endodermal-, mesoderm-, and ectodermal-derived cells [ 40 ].
In addition to the most common adipocytic, chondrocytic, and osteoblastic lineages presented in studies, ADSC can also differentiate into epithelial cells, endothelial cells, liver cells, and nerve cells as well [ 35 ]. This potential is physically essential to support local tissue-specific precursors in faced with damage for tissue regeneration. ADSCs exhibit a longer survival time, stronger proliferative capacity, shorter doubling time, and later in vitro senescence [ 41 ].
ADSC-derived secretome has intrigued increasingly attention in tissue regeneration area. An extensive range of chemokines, cytokines, growth factors, mRNAs, and micro-RNAs are released by ADSCs that participate in angiogenesis, lymphangiogenesis, immune modulation, and reducing fibrogenesis [ 22 , 43 ]. These anti-apoptotic factors and pro-angiogenic factors can affect activities of the nervous system, immune system, heart, muscles, and even ordinary somatic cells through endocrine and paracrine methods and have been demonstrated to play a therapeutic role in bone reconstruction, nerve protection, heart regeneration, and soft tissue regeneration [ 43 , 44 , 45 , 46 , 47 ].
However, the capacity of EVs to secrete growth factors and promote tissue regeneration was indicated not as strong as ADSCs [ 47 ]. ADSCs can also produce antioxidants, free radical scavengers, and heat shock proteins HSP , which promote the repair of viable cells by removing harmful substances from the injured tissue and accelerate wound healing [ 48 , 49 ].
In addition, when stimulated by growth factors or inflammatory molecules, expression profiles of ADSCs may vary accordingly. Due to the pluripotent and paracrine potential, studies have applied ADSCs for cell therapy and tissue engineering in ischemia diseases [ 51 ]. In a myocardial ischemia mouse model, a small portion of ADSCs could differentiate into endothelial cells and vascular smooth muscle cells [ 52 ], as well as cardiomyocytes [ 53 ].
More importantly, high expression of VEGF was detected in the marginal area of the heart infarct zone when treated by ADSCs, thereby improving myocardial function and avoiding adverse ventricular remodeling [ 54 ].
In a cerebral ischemia rat model, infusion of ADSCs conditioned medium CM into the lateral ventricle or vein might reduce the infarct volume and nerve cell apoptosis, promote the proliferation of vascular endothelial cells, and increase the density of microvessels [ 55 , 56 ].
For the avascular necrosis or ulcer wounds caused by diabetes, ADSCs implantation could also obtain a significant therapeutic effect [ 57 ]. In addition, researchers found that external stimulation such as FGF-2 [ 58 ], hypoxia [ 59 ], or recombinant adeno-associated virus rAAV serotype 2 encoding human VEGF [ 60 ] can further enhance the paracrine effect of ADSCs and thus promote angiogenesis.
BM-MSCs can suppress both innate and adaptive immune systems by direct cell-to-cell communication and paracrine cytokines [ 13 ]. PGE2 was reported in vitro to be involved in the inhibition of allogeneic lymphocyte reaction [ 64 ]. Patricia et al. Both in vitro and in vivo results indicated allogeneic ADSCs presented immune tolerance and could not stimulate lymphocyte proliferation, which allows the possibility of ADSCs xenotransplantation [ 73 ].
Preclinical studies and clinical trials have shown that ADSCs have a good therapeutic effect in various autoimmune diseases [ 74 , 75 , 76 ]. Fat tissue is distributed throughout the human body at subcutaneous and visceral depots, such as abdominal, thigh, omentum, and pericardium.
Due to the abundance of fat at subcutaneous sites, the CAL surgeries are always based on ADSCs isolated from abdominal subcutaneous fat or breast.
Recently, the comparative studies begun to explore the differences in ADSCs populations isolated from various anatomical locations. They indicated that ADSCs were influenced significantly by the microenvironment of a specific tissue source in cell phenotype, cell proliferation ability, differentiation ability, and apoptosis susceptibility [ 77 , 78 , 79 , 80 ].
For example, although ADSCs derived from breast fat and abdominal subcutaneous fat are similar in cell phenotype and genetic characteristics, ADSCs from breast fat have higher self-renewal capacity and are more likely to differentiate into osteoblasts, whereas ADSCs from subcutaneous fat are more predisposed to the adipogenic lineage, suggesting that the latter one seems more suitable for fat grafting [ 81 ]. Valerio et al.
The high potential of subcutaneous fat-derived ADSCs to differentiate into adipocytes was consistent with the previous studies [ 79 , 83 ]. Schipper et al. ADSCs from the superficial abdominal depot displayed the lowest apoptosis level, and those derived from young patients presented the highest proliferation capacity [ 78 ].
Jin et al. Therefore, referring to breast reconstruction, it seems more appropriate to utilize ADSCs from young donors and abdominal subcutaneous fat tissue.
Although the role of ADSCs in the development and metastasis of breast cancer has not been fully clarified, it has been concerned for a long time that ADSCs may increase the risk of breast cancer recurrence after CAL-based breast reconstruction. ADSCs primarily exist in fat tissue, as well as the breast cancer microenvironment. The investigators label adipose tissue with GFP and found that ADSCs injected into the circulation or transplanted with adipose tissue could be recruited to breast cancer and further differentiated into vascular endothelial cells, fibroblasts, and pericytes [ 85 , 86 ].
Moreover, ADSCs could selectively home to and engraft into tumor stroma to promote tumor growth and invasion, while filtering organs such as the lung, liver, and spleen were rarely ADSC-enriched, suggesting that tumor was the prerequisite of ADSCs homing and vascular engraftment [ 85 ]. Razmkhah et al.
However, no matter ADSCs were isolated from breast cancer adjacent adipose, benign breast tumor adjacent adipose, or normal breast adipose, all cells were able to promote the proliferation of MCF-7 breast cancer cells in vitro, and cancer-associated ADSCs seemed to exhibit more significant effect than ADSCs from normal fat tissue [ 88 ]. ADSCs can also upregulate the epithelial-mesenchymal transition markers of breast cancer cells, such as fibronectin, alpha smooth muscle actin, and vimentin, and promote the ability of tumor metastasis and invasion [ 89 , 92 , 93 ].
Through paracrine manner by secreting FGF-2 and activating extracellular signal-regulated kinase ERK , ADSCs could drive tumor cell proliferation at the chemo-residual triple-negative breast cancer [ 94 ]. ADSCs might even fuse with tumor cells to form hybrid cells which possessed stronger proliferation and metastasis capabilities [ 95 ].
In contrast, some other studies indicated contradictory results. Donnenberg et al. Kucerova et al. In mouse models, MSCs isolated from adipose and umbilical cord blood even reduced breast cancer lung metastases and induced tumor cell necrosis [ 98 ].
A recent study compared the effects of ADSCs from different breast adipose sources invasive breast cancer, BRCA-mutated invasive breast cancer, ductal carcinoma in situ, healthy controls on multiple breast cancer cell lines and found that ADSCs from invasive breast cancer patients displayed a significant enhancement on the proliferation and metastasis of JIMT in vivo and in vitro, which was HER2-enriched and anti-HER2 resistant, but exhibited a weak promotion effect on T47D and no effect on MDA [ 99 ].
Sakurai et al. Wu et al. ADSC-derived EVs delivered abundant pro-angiogenic factors, which contributed to promoting microvascular endothelial cells to form vessel-like structure in vitro and more neovessels within the fat graft in vivo [ , ]. Lin et al. However, EVs are heterogeneous, and if EVs highly express tumor suppressor molecules such as MiR, they turn into tumor growth inhibitors and might be a potential therapeutic tool [ ].
In general, the influence of ADSCs on the proliferation and metastasis of breast cancer is still inconclusive which might partly owe to the heterogeneity of ADSCs cell population, state of breast cancer cells, and the complicated microenvironment of cancer; therefore, further research is needed. ADSCs can also be educated by tumor cells. Even mature adipocytes are transformed into cancer-associated adipocytes when co-cultured with breast cancer cells, exhibiting an altered phenotype characterized by delipidation, decreased adipocyte markers, and overexpression of proinflammatory cytokines expressing higher levels of pro-inflammatory factors such as IL More signaling pathways related to ADSC activation and re-programming remain to be discovered as future therapeutic targets.
Both autologous transplantation and breast implants are widely used for breast reconstruction. Autologous flap transplantation is the gold standard and provides a quite esthetic, natural, and biocompatible alternative [ ], while it is accompanied with trauma at the donor site, wound cracking, flap necrosis and loss, the risk of abdominal wall hernia, high operating difficulty, and long hospital stay [ ].
Breast prosthesis has become the most commonly used reconstruction technique due to its advantages of short operation time, donor area morbidity-free, and enhanced recovery after surgery, but it also has some defects, such as secondary replacement surgery, repeat prosthesis replacement, prosthesis-related soft tissue infection, capsular contracture, prosthesis displacement, rupture of the prosthesis, and breast implant-associated anaplastic large cell lymphoma [ ].
In contrast, with the development of liposuction applied for obtaining fat tissue, autologous fat graft AFG has become the most promising breast reconstruction technology due to less damage to donor sites.
Even for patients after breast-conserving surgery, the esthetic appearance of the breast could be improved by small volume AFG [ ].
The most important challenge for AFG is to raise the fat survival to get a better appearance, especially for patients who had mastectomy surgery.
Therefore, multiple AFG surgeries are always needed to achieve a satisfactory appearance. Compared with adipocytes, ADSCs are more resistant to ischemia and hypoxia, thus contributing to adipose tissue repair under ischemic conditions [ ]. Therefore, deficiency of multipotent ADSCs might partly explain the predisposition of fat graft to necrosis.
As reviewed above, ADSCs possess a series of features, including being able to differentiate into a variety of cell types including adipocytes; secreting abundant growth factors such as VEGF, HGF, FGF-2, and IGF-1 in a paracrine manner; and modulating immune responses resulting in immune tolerance, which makes ADSCs a perfect alternative for adipose tissue engineering. ADSC-based soft tissue engineering has developed rapidly in the past decades, and ADSCs gradually become the main source of stem cells for adipose engineering including breast reconstruction [ ].
In , Yoshimura et al. It has been well known that ADSCs has lower oxygen consumption and better tolerance than adipose cells when faced with hypoxic environment during fat transplantation. Furthermore, high fraction of ADSCs can also recruit stem cells from other sites, especially the bone marrow, into adipose tissue, and further increase VEGF levels and fat transplant survival [ ].
In summary, for most animal models, including models with immunodeficiency and normal immune, the use of ADSC-based CAL can significantly improve the survival of fat grafts [ , , ].
Due to the extensive expression of estrogen receptor in adipose tissue [ ], Sai et al. However, a lot of details remain clarified and additional studies are needed on the mechanisms and treatment modification of CAL. For example, Ko et al. Li et al. The researchers believed that it took a certain period of time for ADSCs to differentiate into adipocytes and a larger density of ADSCs might not form normal adipose tissue but promoted formation of dense connective tissue at the early stages, which was not in favor of the migration of ADSCs to the perivascular niche or the formation of capillary beds and thus hindered the differentiation of ADSCs [ ], while these hypotheses need future studies to clarify the interaction between ADSCs and microenvironment Tables 1 and 2.
Two years after introduction of CAL, Yoshimura et al. Since then, numerous clinical trials on CAL emerge. Despite encouraging results in animal models, the therapeutic effect of CAL in human breast reconstruction and plastic surgery is still controversial.
Results indicated that fat survival of the ADSC-enriched group was significantly higher than the control group The study conducted by Gentile et al. In contrast, results from Wang et al.
A lot of factors contribute to the variations of results from different studies, including age of fat donor [ ], SVF or ADSCs density, ADSCs isolation technique, fat transplantation surgery process, surgeon skills, and blood supply of the recipient site. Therefore, the isolation of ADSCs from adipose tissue should be as soon as possible and careful operation is very important to improve the therapeutic effect of CAL.
The risk of developing a tumor is rather low in the patients for breast augmentation, and cosmetic appearance is the most important issue. While for breast cancer after oncologic surgery, in addition to cosmetic satisfaction, the most important concern is the oncogenic risk of ADSCs. Breast microenvironment after breast cancer surgery is completely different from a normal breast.
As mentioned above, ADSCs have functions including immune regulation, immunosuppression, cellular homing, pro-angiogenesis, and anti-apoptosis, which endow them not only the application in tissue engineering, but also the possibility to induce breast cancer development and progression.
Therefore, although the role of ADSCs in breast cancer has not been fully elucidated, the application of CAL in breast cancer patients for reconstruction must be cautious and follow-up after surgery should be close. However, the microenvironment of human adipose tissue is much more complicated than conditions of in vitro experiments or animal models; results of preclinical experimental studies cannot be directly adopted for clinical trials.
For example, in recent years, adipocytes have been proved to promote the conversion of androgen to estrogen via expressing aromatase [ ] and alter the tissue environment in a paracrine manner [ ], thus promoting the progress of breast cancer [ ].
However, in clinical practice, the safety of fat grafts has been widely recognized. Studies indicated that fat transplantation does not increase the local tumor recurrence risk in breast cancer patients [ , , , ]. Meantime, results of two studies are noteworthy.
One is a case-control study conducted by Kronowitz et al. This difference might partly attribute to the fact that patients who received lipofilling tend to be elderly, lower tumor stages, and receive more endocrine therapy, which is in line with the real-world situation. Whether there is cross-talk between endocrine therapy and effects of ADSCs remains elucidate.
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