Adipocyte Microenvironment in Ovarian Cancer

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Ana Duarte Mendes	--	3149	2023-12-07 14:47:40	\|
2	format	Jason Zhu	Meta information modification	3149	2023-12-08 02:56:11	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms242316589

Ovarian cancer is one of the most common gynecological malignancies and has low survival rates. One of the main determinants of this unfavorable prognosis is the high rate of peritoneal metastasis at diagnosis, closely related to its morbidity and mortality. The mechanism underlying peritoneal carcinomatosis is not clearly defined, but a clear preference for omental spread has been described. Growing evidence suggests that adipose tissue plays a role in promoting cancer onset and progression. Moreover, obesity can lead to changes in the original functions of adipocytes, resulting in metabolic and inflammatory changes in the adipose tissue microenvironment, potentially increasing the risk of tumor growth.

tumor microenvironment ovarian cancer adipocyte pathogenesis

1. Introduction

Ovarian cancer (OC) ranks as the eighth most prevalent cancer and the fifth deadliest cancer among women globally. Its occurrence is 3.4%, while mortality is 4.7%, resulting in around 200,000 deaths per year due to OC. This highlights the significant disease burden on women’s health and survival ^[1]. Since OC tends to advance rapidly and exhibits no apparent signs or symptoms in its early stages, more than two-thirds of patients are diagnosed at an advanced stage ^[2].

Despite extensive surgical cytoreduction and newer adjuvant treatments, the survival rates for stage III and stage IV remain disappointingly low at 40% and 20%, respectively ^[3]. Within two years, more than half of the patients will experience a relapse, which ultimately results in a detrimental effect on survival rates ^[4].

Peritoneal metastasis is a common occurrence in patients with OC ^[5]. It contributes to malignant ascites accumulation due to the complex tumor-promoting microenvironmental network in the peritoneal cavity. Although the peritoneal cavity is a frequently affected site for OC metastasis, there is still a lack of understanding of the mechanisms related to the proliferation of metastases in the intra-abdominal environment. The intricacies of the tumor microenvironment (TME) within the peritoneal cavity and intra-abdominal metastasis remain poorly understood. Comprised of various cell types, including tumor and host stromal cells, blood vessels, and the extracellular matrix (ECM), the TME’s role in OC cell dissemination is yet uncertain. Nevertheless, research suggests that the interaction between tumor and stromal cells may facilitate OC cell spread within the peritoneal cavity ^[6]^[7].

2. Peritoneal Microenvironment and OC Peritoneal Metastasis

The mechanisms that enable OC to easily spread to the peritoneum through tumor-stromal cell interaction in the TME are not well understood.

The peritoneal cavity holds serous exudate, which includes steroid hormones, cytokines, and growth factors. The amount of peritoneal fluid in humans can range from 5 to 20 mL and may vary based on the individual’s physiological state ^[8]. Notably, macrophages are the most abundant immune cell population in peritoneal fluid, followed by smaller populations of T, dendritic, mast, NK, and B cells ^[9].

The peritoneal fluid provides a metastatic milieu for OC. The microenvironment of ascites is particularly conducive to this process, allowing these cells to disseminate and seed within the peritoneal cavity. Even when detached from the primary tumor, these cancer cells can persist within the ascites by overcoming various obstacles, including spheroid formation, resistance to anoikis, and immunological surveillance ^[7]^[10].

The deregulation of the expression of surface proteins, such as integrin and fibronectin, facilitates the aggregation of tumor cells. In vitro studies have shown that the upregulation of integrin α5 in tumor cells favors the formation of aggregates between these cells and fibroblasts, contributing to the early stages of peritoneal dissemination. These mechanisms are yet to be fully understood ^[11].

After detachment from the primary sites, OC cells acquire anoikis resistance to survive within the peritoneal cavity. This process of resistance is related to the ability of tumor cells to overcome the process of apoptosis after losing connections with the cellular matrix of the primary site ^[12]. Several molecular processes are involved in this mechanism of tumor cell resistance, namely Ras-related protein Rab-25 (RAB25) small GTPase, integrin members, and leucine rich repeat containing 15 (LRRC15) ^[9].

In the TME, immune modulation by tumor cells in the peritoneal cavity is one of the most important mechanisms for survival and proliferation. In peritoneal fluid, the detection of high levels of inflammatory cytokines such as IL-2 and TNF are indicators of tumor cell activity ^[13]. Besides, OC cells in ascites induce apoptosis of CD95-positive immune cells and could also recruit regulatory T cells (Treg) and inhibit specific anti-tumor immunity, promoting tumor progression ^[14].

The omentum is the fused peritoneal fold nestling on the surface of the intra-peritoneal Worgans. It is a critical component in immune regulation by managing inflammation, fluid exchange, promoting angiogenesis, and regulating adipogenesis. Beneath its mesothelial cell covering lays adipocytes, adipose-derived stromal cells, fibroblasts, and immune cells ^[15]. Milky spots are lymphoid structures found in the omentum, which consists mainly of macrophages, T cells, and B cells. It is worth noting that the mesothelial lining in these spots is not continuous, which allows leukocytes to relocate into the peritoneal cavity.

Various cells play an essential role in shaping the TME of the peritoneal cavity, namely tumor cells, stromal cells, adipocytes, and immune system cells. The preparation of the pre-metastatic niche, a crucial component for the spread of OC, is facilitated by the interaction between tumor cells and stromal cells in the omentum ^[16].

The tumor cells are of utmost significance among these cells, as they create pre-metastatic niches and trigger a mesothelial-to-mesenchymal transition (MMT). Ordinarily, mesothelial cells serve to prevent cancer cell adhesion to the peritoneum. However, when MMT occurs, they foster adhesion and metastasis. Fibroblasts serve as primary ECM regulators, but they can also promote metastasis by transforming into cancer-associated fibroblasts (CAFs). Although the precise mechanisms behind this transformation are not yet fully understood, the impact of CAFs is unmistakable. They facilitate peritoneal metastasis by regulating the ECM, secreting cytokines, TGF-β, and vascular endothelial growth factor (VEGF) ^[17]. The extensive proliferation of the ECM in peritoneal carcinomatosis associated with OC poses a significant challenge for systemic therapy penetration. Tumor cells can induce MMT of peritoneal mesothelial cells, resulting in further ECM proliferation ^[18]. Studies have revealed that OC cells manipulate the TME by regulating the ECM, facilitating a favorable tumor growth environment ^[19]. This regulation can be conducted by an aberrant transforming growth factor beta (TGF-β) pathway. TGF-β can be released from tumor cells, contributing to regulating epithelial-to-mesenchymal (EMT) transition and metastatic niche formation. Studies have shown that high-grade OC exhibits a high level of amplification in the TGFβ pathway. Research suggests that all three isoforms are elevated in primary, metastatic, and recurrent EOCs compared to normal ovaries. The fallopian tube, one of the sites of tumor initiation and early metastasis of high-grade serous OC, expresses the TGFβ isoforms and their receptors. Interestingly, while tumor cells are a source of TGFβ in OC, the peritoneal mesothelium and tumor-infiltrating cells also contribute to its production. Tumor cells in the peritoneal environment have been found to interact with mesothelial cells through TGFβ signaling. This signaling pathway is mediated by cancer-derived TGFβ1. As a result, the expression of fibronectin is increased in peritoneal mesothelial cells ^[20].

Cancer antigen 125 (CA125) is a serum tumor marker commonly used in clinical practice. It is a glycoprotein overexpressed on OC cells that promotes the adhesion of OC cells into the peritoneal mesothelial layer through binding to mesothelin ^[21].

The basement membrane of peritoneal tissues is rich in collagen and fibronectin. The disseminated OC cells’ overexpression of matrix metalloproteinases (MMP), like MMP2, facilitates the connection to peritoneal mesothelium through cleaving fibronectin and vitronectin ^[18]. In addition, OC cells can attach to the peritoneal mesothelium by regulating hyaluronan expression on mesothelial cells.

The immune system also plays a pivotal role in the pathogenesis of OC. Infiltration of regulatory T-cells (Tregs), a subset of T-cells, has been associated with worse outcomes due to impaired anti-tumor immune response. Tregs release TGF-β, which supports the TME ^[17]. Macrophages in the peritoneal cavity also play an essential role. In normal circumstances, various macrophage populations are present in the peritoneal fluid and peritoneum, each with unique traits ^[10]. However, tumor-associated macrophages have distinct characteristics and are believed to promote tumor advancement ^[22]^[23].

Macrophage-derived cytokines, such as TGF-β1 and macrophage inflammatory protein one beta (MIP-1β), promote cancer cell adhesion, invasion, and proliferation ^[24].

Recent studies reveal that tumor cells can thrive on nutrients from adipocytes found in peritoneal metastases ^[25].

The TME is widely recognized as a key factor in the development and progression of tumors throughout the body. In fact, several therapies targeting the TME have been extensively described ^[26]. This complex network includes a variety of cells, including lymphocytes, antigen-presenting cells, cancer fibroblasts, and the ECM. When an individual becomes overweight, chronic inflammation and hypoxia of the AT can negatively impact this environment, leading to damage to its intricate connections and an increased risk of cancer ^[27].

3. Obesity and Adipogenesis

Adipose tissue, the primary component of the human body, is a loose connective tissue typically situated beneath the skin. However, it can also be deposited in muscles, intestines, omentum, and bone marrow. The functional classification of AT distinguishes between energy-storing white adipocytes, the predominant cell type of white AT (WAT), and thermogenically active brown adipocytes in brown AT, which have distinct cellular organizations and different biological and physiological functions ^[28]. The location within the human body also significantly alters its function: the accumulation of visceral WAT, particularly in the omentum and mesentery, during weight gain, is strongly correlated with the development of insulin resistance and metabolic syndrome, as opposed to subcutaneous WAT accumulation ^[29].

Apart from the adipocyte itself, the AT niche is a complex biological entity made up of various cells, including endothelial cells, macrophages, immune cells, and stem cells within adipose stromal cells. Together, these cells work in harmony with secreted factors and ECM to regulate AT homeostasis and remodeling ^[16].

Initially, adipocytes, the core elements of AT, were believed to function only as storage units for energy. In 1994, AT was recognized as a secreting organ for producing the hormone leptin ^[30], and over 400 additional factors secreted by adipocytes, known as adipokines, have been identified. These adipokines include hormones like adiponectin, leptin, and resistin, as well as inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-8, enzymes like 17β-hydroxysteroid dehydrogenase (17βHSD) and 11βHSD1, and other factors. Unfortunately, some adipokines, such as IL-6, IL-8, and leptin, have been found to hasten certain tumors’ growth, metastasis, and drug resistance ^[31]^[32].

Obesity is a pathological condition that results in excessive AT growth. It is a widespread problem that is linked to all causes-morbidity and mortality rates, with growing evidence linking obesity to cancer. The World Health Organization has classified it as a non-infectious and non-communicable pandemic ^[33]. Regarding field of work, a global study suggested that young women between the ages of 15–40 in certain countries are more susceptible to OC due to elevated obesity and metabolic syndrome rates ^[34]. Numerous studies utilize plain indicators of obesity, such as body mass index (BMI) or waist circumference, which do not consider the intricate biology involved in being overweight or obese. Although the quantity of fat tissue in the body is associated with an increased risk of disease, it is also crucial to consider the quality of that tissue, including elements like inflammation, adipocyte hypertrophy, and hypoxia ^[35].

In the process of weight gain, lipids accumulate in the adipocytes, becoming hypertrophic and ultimately dying. The death of these cells triggers immune system, accumulating immune cells in the area and can modulate the microenvironment to a state of chronic low-grade inflammation. The inflammation has mainly been attributed to areas of AT where infiltrating macrophages surround the dying adipocytes to form crown-like structures (CLS). These structures, existing in most AT, show greater frequency in visceral AT than in subcutaneous tissue, and their number increase with body mass index ^[36]^[37]. This process can cause changes in the adipokine profile, which includes a decrease in adiponectin and an increase in leptin, TNF-α, and IL-6. These changes can lead to metabolic and inflammatory alterations in the AT, creating dysfunctional adipocytes and, thus, a favorable environment for tumor development, resulting in a worse cancer prognosis ^[38]^[39]. The association of CLS with worse outcomes in cancer patients leads to increased interest as a prognostic biomarker ^[40]. Aside from the CLSs, various granulocytic cells become active within the myeloid compartment. Neutrophils, highly associated with cancer, rapidly increase in WAT after three days of a high-fat diet. This increase triggers the release of the protease neutrophil elastase, which breaks down insulin receptor substrate 1 (IRS1). This prevents IRS1 from binding to phosphoinositide 3-kinase (PI3K), which leads to insulin resistance. This resistance can promote epithelial cell proliferation, which may act as a surrogate mechanism of PI3K activation in wild-type tumors through its inductive effects on insulin. Although granulocyte dynamics initially help control inflammation during weight gain, they may lower the threshold to malignant transformation by impairing immune surveillance ^[41]^[42].

In AT growth, the capillary networks become insufficient to match the needs. This effect results in areas of hypoxia that simulate the ones present in developing tumors. Both obesity and cancer are linked to hypoxia, which triggers the production of pro-angiogenic factors like VEGF and hypoxia-inducible factor 1 subunit alpha (HIF-1α). HIF-1 is critical in various aspects of cancer, such as angiogenesis, stem cell maintenance, metabolic reprogramming, metastasis, and resistance to radiation and chemotherapy. However, even with the angiogenic stimulus, hypoxia in obesity cannot be fully reversed, resulting in persistently low oxygen levels due to poorly functioning blood vessels. This chronic condition leads to adipocyte death, promoting macrophage infiltration ^[43]^[44].

Beyond the low-grade chronic inflammation as a bridge to oncogenesis, obesity also plays a crucial role in insulin resistance syndrome. This syndrome has been known to promote cancer development by affecting insulin receptors directly or indirectly by impacting other modulators, such as the insulin-like growth factor (IGF) family of receptors. Adipocytes release IGF-I, a vital growth factor that sustains their differentiation and metabolic regulation. However, altered levels of IGF-I may stimulate tumor malignancies. IGF-1 binds to IGF-1R, a tyrosine kinase receptor, which activates downstream signal effectors, including Ras/Raf/ERK and PI3K/Akt/mTOR. These effectors play a crucial role in cell growth, proliferation, and various types of cancers. AT is also involved in synthesizing a broad range of bioactive molecules, among which adipokines, a group of peptides mainly produced by AT, have emerged as a significant link between obesity and cancer. Adiponectin is the most abundant adipokine in plasma, and its secretion is strongly related to the circulating levels of other hormones. Interestingly, an inverse association between adiponectin and fasting plasma insulin has been demonstrated. Low levels of adiponectin have been associated with obesity and insulin resistance. Conversely, several pieces of evidence have shown that leptin, whose circulating levels increase proportionally with fat mass, directly or indirectly affects the biology of several cancers. In summary, obesity has been recognized as a potential promoter of cancer growth through several mechanisms ^[45].

Interestingly, there is also a role for gut microbiota and obesity. Recent research has highlighted the significance of gut microbiota in the pathogenesis of various diseases. Gut microbiota refers to the diverse microorganisms that inhabit the human gut tract. The correlation between the onset and progression of obesity and gut microbiota is well-established; however, the precise association and underlying mechanisms remain elusive. An insightful review by Cheng et al. analyzed the existing data. It revealed that dysregulated microbiota can contribute to obesity through several channels, including disruption of energy homeostasis, lipid metabolism, and chronic low-grade inflammation ^[46].

4. Adipocytes in Ovarian Cancer

Cancer cells tend to develop in the omental milky spots within peritoneal fat depots ^[47].

OC cells closely interact with adipocytes in the omentum, leading to significant phenotypic alterations in the adipocytes. These altered adipocytes, with different characteristics from those of primary adipocytes, are named cancer-associated adipocytes (CAAs) ^[48]^[49]. Unlike typical adipocytes, CAAs possess a smaller size, decreased lipid content, and lower levels of adipocyte differentiation markers. Conversely, they exhibit higher levels of adipokines and inflammatory factors such as leptin, MMP-11, chemokine ligand (CCL) 2, CCL5, and IL-6.

The current understanding is that CAAs are multifaceted and constantly evolving, having many roles in constructing a tumor-promoting microenvironment ^[50].

The various roles are linked to crucial areas: creating a vast ECM, inducing a senescent-like phenotype, exchanging high-value and high-energy metabolites, and immune regulation.

The extensive ECM in CAAs may be related to an adipocyte-derived overexpression of collagen VI ^[51]. Prolonged exposure to OC leads to the accumulation of CAAs with brown/beige differentiation and fibroblastic characteristics, thereby significantly reinforcing tumor development ^[52].

CAAs can remarkably halt the cell cycle while increasing the expression of genes related to cell cycle arrest and decreasing the expression of genes promoting cell growth. Furthermore, it is to be noted that the transition from normal adipocytes to CAAs may encounter cellular aging due to the activation of multiple oncogenes ^[53]. Caveolin-1 (Cav-1)- the major scaffold protein of caveolae (crucial membrane microdomains)—which plays a crucial role in membrane transport, lipid composition preservation, and signal transduction within cells, has been suggested as a tumor suppressor and a decrease in its expression can promote tumor growth and metastasis. Autophagy induced by Cav-1 may play a crucial role in the interaction between CAAs and cellular senescence ^[54].

Stromal adipocytes can also interact with cancer cells by exchanging metabolites and amino acids. Extracellular vesicles (EVs) act as messengers between adipocytes and cancer cells, carrying proteins and substrates involved in fatty acid oxidation (FAO) to tumor cells. In obesity, EVs can transport fatty acids and store lipid droplets in cancer cells. The metabolic disorder of CAAs may be linked to altered immunoregulation, possibly through the promotion of FAO or the intake of immunomodulatory amino acids ^[55]^[56].

CAAs are crucial in producing various substances such as adipokines, chemokines, cytokines, and exosomes. These can have a significant impact on tumor growth and treatment efficacy. CAAs release chemicals such as CCL2, CCL5, IL-1β, IL-6, TNF-α, VEGF, and leptin, facilitating tumor spread and evading the immune system. Leptin, in particular, has been shown to influence the immune system, as noted in a review by Naylor et al. ^[57]. Additionally, CCL2 and CCL5 can attract and modify the behavior of macrophages in AT, known as AT macrophages (ATMs), through the release of exosomes. ATMs have been associated with the production of various inflammatory substances ^[58], and their accumulation is frequently associated with adverse outcomes and resistance to cytotoxic therapy ^[59].

Adipocytes in brown AT play an immunosuppressive role by expressing programmed death-ligand 1 (PD-L1). This internal pool of PD-L1 could impact antitumor immunity. In vitro, adipocyte surface PD-L1 could interact with T cell surface PD-1 to debilitate the antitumor role of T cells. In vivo, adipocyte PD-L1 could dampen interferon (IFN)γ production of CD8+ T cells. Furthermore, adipogenesis inhibition selectively decreased the PD-L1 expression in AT and enhanced the antitumor effect of anti-PD-L1 or anti-PD-1 antibodies ^[60].

Given OC’s unique adipocyte-rich metastatic niche, the adipocytes’ immunosuppressive role could explain the low response to checkpoint blockade immunotherapies ^[61]. It should be noted, however, that the relationship between obesity and response to PD-1 blockade is not completely understood, as the high efficacy of immune checkpoint inhibitors in obese men with melanoma has been described ^[62].

The evidence is mounting—adipocytes are actively involved in cancer progression.

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