Adipose-Derived Stems Cells and Their Role in Human Cancer Development, Growth, Progression, and Metastasis: A Systematic Review Free

Obesity is reaching epidemic proportions in the United States, affecting more than one third of the population (1). It is a risk factor for cardiovascular disease, type II diabetes, as well as many different human cancers, including breast (2), colon (3), endometrial (demonstrating the most elevated risk; refs. 4–6), and other malignancies (7). Furthermore, women appear to evidence higher incidence of cancer due to obesity compared with men. According to the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database, in 2007, approximately 4% of cancer cases in men and 7% of cancer cases in women were attributable to obesity (8). Existing research linking obesity and cancer risk is predominantly focused on investigating epidemiologic risk factors as well as systemic and local tissue biomarkers (5). However, in recent years, a growing body of literature has explored how obesity leads to physiologic changes of adipose tissue itself.

Adipose tissue has notable plasticity throughout life (9) and is a highly active endocrine organ (10). It contains adipocytes, connective tissue matrices, nerve tissue, stromovascular cells, and immune cells (11). Excess adiposity leads to chronic, low-grade inflammation, which, among other factors, has been implicated in cancer development (12–17). Increasing adiposity may act via the dysregulated secretion of proinflammatory cytokines, chemokines, and adipokines to contribute to the development of cancer. Specifically, these include TNFα, IL6, leptin, adiponectin, visfatin, and plasminogen activator inhibitor (PAI)-1 (18–20).

Adipose-derived stem cells (ASC) are present within the stromal vascular fraction of adipose tissue and have tremendous plasticity. They have the ability to differentiate into numerous cell lineages, including adipogenic, osteogenic, chondrogenic, myogenic, cardiomyogenic, and neurogenic-like cell types (9, 21–25). They have been associated with expressing/secreting multiple important growth factors, cytokines, chemokines, and inflammatory biomarkers linked to cancer development and progression, including insulin-like growth factor (IGF), hepatocyte growth factor (HGF), TGFβ1, VEGF, IL8, Bcl-2, and IL10 (26–34). In addition, cancer cells, peritumoral adipocytes, and ASCs are thought to interact with one another, leading to more aggressive tumor behavior. In 2011, Dirat and colleagues reported that peritumoral adipocytes appear to exhibit modified phenotypical and biologic characteristics as a result of invasive cancer cells. These “cancer-associated adipocytes” in turn modify cancer cell behavior (35). Finally, adipose tissue is a significant source of circulating blood estrogen, with which body mass index is positively correlated (36). Estrogen-dependent pathways, such as those utilizing estrogen receptor-alpha (ESR1), change the biology of ASCs, potentially leading to modified behavior of the tumor and surrounding tissue.

Although there is a growing body of literature exploring the role of ASCs in the development of various human cancer types, no known review exists presenting the accumulated knowledge in this field in a systematic manner. Furthermore, ASCs' role in cancers primarily affecting women is a growing topic of interest in the research and clinical communities. Therefore, the purpose of this systematic literature review is to explore and summarize existing knowledge on the potential role of ASCs in cancer development, growth, progression, and metastasis. We place special emphasis on cancers affecting women, as malignancies such as endometrial cancer and postmenopausal breast cancer are especially sensitive to increasing adiposity.

A search of the bibliographic resource PubMed was performed in June 2014. A combination of keywords relating to ASCs used in the literature search included: adipose-derived stem cells, ASCs, ASDCs, adipose-derived stromal cells, adipose mesenchymal cells, and cancer. Additional searches were performed that included specific malignancy terms. Figure 1 illustrates our search strategy.

Articles were included in this review if they were published between 2001 and 2014, as 2001 appeared to be the first reference to processed lipoaspirate (PLA) cells (37), an early term for ASCs. All studies included in this review were published in English or had an expanded abstract in English. Investigations that used mixed animal and human cells in vivo were included, for example, those using human ASCs in mice to study tumor behavior (38, 39). Special attention was given to peer-reviewed articles that explicitly addressed the relationship between human cancer development, growth, metastasis, and ASCs. In addition, while we recognize that adipose tissue comes from several different depots (such as subcutaneous and visceral), we did not restrict this review to any one particular depot due to the paucity of literature in the area.

Exclusion criteria were as follows: the article's primary focus was not ASCs and their relationship to cancer, exclusively used animal models, addressed malignancies restricted to men (i.e., prostate), tested drug delivery systems instead of ASC behavior in relationship to cancer, tested tissue regeneration and cell therapy, or did not indicate that main outcome measure was not tumor development, growth, progression, and metastasis.

Of 197 initially identified articles, 37 eligible articles were included in the final review based on inclusion and exclusion criteria. We divided this review into two main areas: cancer types [typically] specific to women (Table 1) and cancer types nonspecific to women, but not restricted to men (Table 2). Figure 2 summarizes the various mechanisms by which ASCs may influence tumor development, progression, growth, and metastasis. Moderation of these reactions appears to be driven by both, positive feedback from factors such as inflammation and angiogenesis and the tumor microenvironment itself.

There remains controversy regarding the mechanisms by which ASCs influence tumor development, growth, progression, and metastasis; however, many of the articles identified in our review implicate ASCs in influencing tumor microenvironment. Ilmer and colleagues reported on the duality of ASCs—that they display regenerative properties but are also implicated in tumor growth and progression (40). Other authors have reported that ASCs may be protective, particularly in suppressing tumor growth and stimulating apoptosis. Most of the articles reviewed consistently pointed out that the role of ASCs in tumor development is complex, and that the tumor microenvironment milieu in which ASCs are present and the mechanisms by which they migrate may influence their role in cancer development (41–45).

Previous research has demonstrated that ASCs differentiate into various cell types such as endothelial cells, vascular complexes, and tumor stroma, facilitating tumor growth (26, 46–49). A variety of biologic pathways have been suggested regarding the ways by which ASCs are recruited. The stromal-derived factor-1/CXC receptor-4 (SDF-1/CXCR4) axis is implicated (50–52), as are various inflammation-associated chemokines and cytokines. These are released by both the tumor microenvironment and ASCs and may guide ASC migration and incorporation (47). Razmkhah and colleagues reported that ASCs express IL4, IL10, IL8, matrix metallopeptidase (MMP)-2, VEGF, and SDF-1 (27), which promoted anti-inflammatory reactions, potentially playing a crucial role in breast tumor growth and progression.

Tumor growth and metastasis formation are dependent on the growth of blood vessels into the tumor mass, and the tumor microenvironment plays an important role in this pathologic angiogenic process (53). Adipokines secreted by ASCs have been implicated in tumor growth by promoting vascularization, a necessary component of expanding tumor mass (54). Expression of VEGF in ASCs increases in hypoxic environments, which promotes angiogenesis (55).

ASCs express growth factors that lead to increased vascularization within a variety of tumor types and pathways. Gehmert and colleagues (56) reported that ASCs may contribute to angiogenesis by migrating toward tumor-conditioned media through the platelet-derived growth factor-BB/platelet-derived growth factor receptor-B (PDGF-BB/PDGFR-B) signaling pathway. Several investigators published on the production of VEGF by ASCs; Razmkhah and colleagues (27) reported that in ASCs, relative quantifications of VEGF were two times higher in breast cancer tissue than in controls. In addition, Zhao and colleagues (57) reported that ASCs chemoattract endothelial cells by a VEGF-dependent method. Jeon and colleagues (58) showed that the lysophosphatidic acid (LPA)–LPA1 signaling pathway played a key role in ASC differentiation and VEGF-mediated angiogenesis, Akimoto and colleagues (59) illustrated that ASCs may support glioblastoma multiforme by promoting angiogenesis, and Klopp and colleagues (60) suggested that through expressing various, specific factors, omental ASCs increase tumor vascularization in endometrial cancer.

Differentiation of ASCs to carcinoma-associated fibroblasts has been reported by a number of investigative teams. In breast cancer tumor models, Chandler and colleagues (48), Cho and colleagues (61), and Jotzu and colleagues (62) found that ASCs, when induced by factors within the tumor microenvironment, may differentiate into fibroblasts and promote tumor proliferation. Similarly, Cho and colleagues (63) and Jeon and colleagues (64) demonstrated a similar phenomenon in ovarian cancer. Do and colleagues (65) and Park and colleagues (66) illustrated this concept in lung cancer progression.

Several mechanisms linking ASCs and tumor development/progression have been described, with many studies highlighting the importance of tumor environment modification by ASCs (41–44). ASCs may play a role in the creation of an inflammatory tumor microenvironment, which promotes tumorigenic activity. Eterno and colleagues (44) suggested that ASCs may worsen tumorigenic behavior of c-Met producing breast cancer cells by creating a tumor microenvironment characterized by inflammation. The TGFβ1 signaling pathway may also play a role in the way ASCs interact with the tumor microenvironment (41). In addition, as tumor microenvironment is often hypoxic, we hypothesized that there should be a body of publications describing interconnections between ASCs and hypoxia; however, we found little mention of this research area within the existing literature.

Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, playing an important role in tumor physiology and cancer treatment (67). Previous research in the area of ASCs demonstrated that growth conditions utilizing a xeno-free and hypoxic environment provide an improved environment for the expansion of these cells (68). Animal studies suggested that adipose tissue is hypoxic and that local adipose tissue hypoxia dysregulates the production of adipocytokines (69). Human studies have also shown that adipose tissue is hypoxic; obesity results in reduced adipose tissue oxygenation, which is evidence for rarefaction, macrophage chemotaxis, and inflammation with an angiogenic response (70). Adipose tissue hypoxia may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress, and mitochondrial dysfunction in white adipose tissue in obesity (71). Thus, future research efforts should explore the impacts of hypoxic tumor microenvironments in relation to tumor growth and progression.

Both the total volume of excess adipose tissue and more specifically, abdominal (visceral) adipose tissue, has been shown to be associated with metabolic risk factors, cardiovascular disease (CVD), and cancer of the colon (72), breast (73, 74), and endometrial cancers (75, 76) rather than the total amount of body fat (77, 78). ASCs derived from the abdominal subcutaneous adipose tissue of obese subjects (body mass index ≥ 30 kg/m²) promoted breast cancer cell proliferation in vitro and tumorigenicity in vivo (79). These findings were correlated with changes in the gene expression profile of breast cancer cells after coculturing with ASCs, particularly in estrogen receptor-alpha (ESR1). Other published studies in the area of breast cancer have shown that gene expression of IL10 and TGF-β1 in ASCs was significantly greater than in adipose tissue of normal subjects (41).

Endometrial cancer is the most common gynecologic malignancy uniquely sensitive to obesity. While many cancers are well studied in relation to ASCs, there is a paucity of literature on the relationship between ASCs and endometrial cancer. Only one study was identified in the current review, which was a surprising finding because endometrial cancer is strongly associated with obesity and changes in adiposity (80). Klopp and colleagues investigated whether intra-abdominal visceral adipose tissue contained more endometrial tumor–promoting ASCs as compared with subcutaneous ASCs (60). Klopp and colleagues (60) utilized mouse modeling to measure chronic recruitment of ASCs by tumors; their findings suggested that visceral fat ASCs potentially promote more endometrial tumor growth than ASCs from subcutaneous fat. Because numerous articles implicate ASCs in hormonally driven cancers (such as breast), our expectation is that future studies would evaluate the link between ASCs and endometrial cancer (closely linked to excess unopposed estrogen). In addition to the well-established unopposed estrogen link, endometrial cancer risk has been linked to insulin resistance/metabolic syndrome, steroids, and inflammatory factors (81). Although all these mechanisms were also found to be important for general cancers, we speculate that ASCs may play an even more profound effect in endometrial cancer and may potentially be used as an endometrial cancer biomarker.

This study demonstrated that there is a wide breadth of available literature on the relationship between ASCs and cancer development, including mounting evidence in the areas of ASCs' role in the growth, progression, and metastasis of various malignancies (82–84). It appears that ASCs potentially play a role in multiple processes affecting tumor microenvironment; however, few articles specifically address the influence of ASCs on tumor microenvironment. For example, there are gaps in the available literature regarding potential hypoxic mechanisms in relation to ASCs, as well as little discussion addressing the role of ASCs in gynecologic malignancies, specifically endometrial cancer. Because adipose tissue appears to be a key to endometrial cancer development and has not been thoroughly evaluated in patients with endometrial cancer, future research should aim to bridge this gap and identify potential mechanisms implicated in endometrial cancer development, growth, progression, and metastasis in relation to ASCs (85). Future studies should also focus on better describing the differences between various depots of adipose tissue, including identifying differences in ASCs found between subcutaneous, omental, and retroperitoneal adipose tissues. An improved understanding of the underlying biologic mechanisms associated with adiposity and human malignancies, specifically among women's cancers such as endometrial cancer, may hold a key to better preventive strategies and improved screening programs.

No conflict of interest and no commercial interest reported.