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To identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.

Breast cancer is the main cause of morbidity and mortality in women worldwide. However, the molecular pathogenesis of breast cancer remains poorly defined due to its heterogeneity. Several studies have reported that G Protein-Coupled Estrogen Receptor 1 (GPER1) plays a crucial role in breast cancer progression, by binding to estrogens or synthetic agonists, like G-1, thus modulating genes involved in diverse biological events, such as cell proliferation, migration, apoptosis, and metastasis. In addition, it has been established that the dysregulation of short sequences of non-coding RNA, named microRNAs (miRNAs), is involved in various pathophysiological conditions, including breast cancer. Recent evidence has indicated that estrogens may regulate miRNA expression and therefore modulate the levels of their target genes, not only through the classical estrogen receptors (ERs), but also activating GPER1 signalling, hence suggesting an alternative molecular pathway involved in breast tumor progression. Here, the current knowledge about GPER1 and miRNA action in breast cancer is recapitulated, reporting recent evidence on the liaison of these two players in triggering breast tumorogenic effects. Elucidating the role of GPER1 and miRNAs in breast cancer might provide new tools for innovative approaches in anti-cancer therapy.

Yuqi Yang,1 Sheng Yin,2 Shuqing Li,3 Yaping Chen,1 Lina Yang11Department of Obstetrics and Gynecology, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, People’s Republic of China; 2Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of ChinaBackground: Tumor metastasis is the major challenge for ovarian cancer treatment. Cancer-associated fibroblasts (CAFs), a major component existing in tumor microenvironment, can secrete several cytokines to interact with cancer epithelial cells, and promote cancer metastasis. Stanniocalcin 1 (STC1), a secretory glycoprotein hormone, has been proven to be an important factor in ovarian tumorigenesis.Methods: In this study, we focused on the functional role of STC1 in ovarian cancer microenvironment, investigated STC1’s effects on the proliferation and metastasis of ovarian cancer cells, and explored the molecular mechanism underlying STC1-mediated cancer metastasis.Results: By analyzing the GEO dataset and examined STC1 expression in CAFs isolated from ovarian cancer patients, we found that expression of STC1 was higher in ovarian cancer stroma and CAFs than in the normal ovarian stroma and normal fibroblasts (NFs). Addition of recombinant human STC1 (rhSTC1) promoted cell proliferation and metastasis in ovarian cancer, while adoption of STC1 neutralizing antibody (STC1 Ab) abolished the effects. Furthermore, our results revealed that STC1 promoted the phosphorylation of Akt (Ser473), and upregulated several epithelial–mesenchymal transition (EMT) markers including fibronectin，vimentin and slug. In addition, we demonstrated that STC1 in tumor microenvironment could mediate the conversion of NFs to CAFs.Conclusion: Taken together, the study results suggested the crucial role of STC1 in tumor environment on the metastasis of ovarian cancer.Keywords: STC1, tumor microenvironment, CAFs, EMT, metastasis

Solid tumors consist of various types of stromal cells in addition to cancer cells. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma and play an essential role in tumor progression and metastasis in a variety of malignancies, including gastric cancer. However, the effects of CAFs on gastric cancer cells' progression and metastasis are not well studied. Here we show that matrix metalloproteinase 11 (MMP11) in exosomes secreted from CAFs can be delivered into gastric cancer cells. Gastric CAFs promote gastric cancer cell migration partially through exosomal MMP11. Moreover, MMP11 is overexpressed in exosomes purified from plasma of gastric cancer patients and tumor tissues and associated with overall survival of gastric patients. We also find that MMP11 is negatively regulated by exosomal miR-139 in the CAFs of gastric cancer. Exosomal miR-139 inhibits tumor growth and metastasis of gastric cancer cells by decreasing the expression of MMP11 in vitro and in vivo. Thus, we propose that exosomal miR-139 derived from gastric CAFs could inhibit the progression and metastasis of gastric cancer by decreasing MMP11 in tumor microenvironment.

Cancer-associated fibroblasts cells (CAFs) confer a rapid growth and metastasis ability of endometrial cancer (EC) via exosomes-mediated cellular communication. Long non-coding RNA nuclear enriched abundant transcript 1 (lncRNA NEAT1) drives the malignant phenotypes of EC cells. However, the role of exosomal NEAT1 from CAFs in EC progression remains ambiguous, which needs to be investigated. In our study, NEAT1 and YKL-40 were up-regulated, while miR-26a/b-5p was down-regulated in EC tissues. Moreover, NEAT1 expression was increased in CAF-exosomes compared with that in NF-exosomes. In addition, the exosomal NEAT1 derived from CAFs could transfer to EC cells and promote YKL-40 expression. Further exploration showed that exosomal NEAT1 enhanced YKL-40 expression via regulating miR-26a/b-5p-STAT3 axis in EC cells. More importantly, exosomal NEAT1 accelerated in vivo tumor growth via miR-26a/b-5p-STAT3-YKL-40 axis. Taken together, our study reveals that exosomal NEAT1 from CAFs contributes to EC progression via miR-26a/b-5p-mediated STAT3/YKL-40 pathway, which indicates the therapeutic potential of exosomal NEAT1 for treating EC., Graphical abstract Image, graphical abstract

Cancer cells resistance to various therapies remains to be a key challenge nowadays. For a long time, scientists focused on tumor cells themselves for the mechanisms of acquired drug resistance. However, recent evidence showed that tumor microenvironment (TME) is essential for regulating immune escape, drug resistance, progression and metastasis of malignant cells. Reciprocal interactions between cancer cells and non-malignant cells within this milieu often reshape the TME and promote drug resistance. Therefore, advanced knowledge about these sophisticated interactions is significant for the design of effective therapeutic approaches. In this review, we highlight cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory lymphocytes (Tregs), mesenchymal stem cells (MSCs), cancer-associated adipocytes (CAAs), and tumor endothelial cells (TECs) existing in TME, as well as their multiple cross-talk with tumor cells, which eventually endows tumor cells with therapeutic resistance.

The tumor microenvironment (TME) has an essential role in tumor initiation and development. Tumor cells are considered to actively create their microenvironment during tumorigenesis and tumor development. The TME contains multiple types of stromal cells, cancer-associated fibroblasts (CAFs), Tumor endothelial cells (TECs), tumor-associated adipocytes (TAAs), tumor-associated macrophages (TAMs) and others. These cells work together and with the extracellular matrix (ECM) and many other factors to coordinately contribute to tumor growth and maintenance. Although the types and functions of TME cells are well understood, the origin of these cells is still obscure. Many scientists have tried to demonstrate the origin of these cells. Some researchers postulated that TME cells originated from surrounding normal tissues, and others demonstrated that the origin is cancer cells. Recent evidence demonstrates that cancer stem cells (CSCs) have differentiation abilities to generate the original lineage cells for promoting tumor growth and metastasis. The differentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity. Using induced pluripotent stem cells (iPSCs), our group postulates that CSCs could be one of the key sources of CAFs, TECs, TAAs, and TAMs as well as the descendants, which support the self-renewal potential of the cells and exhibit heterogeneity. In this review, we summarize TME components, their interactions within the TME and their insight into cancer therapy. Especially, we focus on the TME cells and their possible origin and also discuss the multi-lineage differentiation potentials of CSCs exploiting iPSCs to create a society of cells in cancer tissues including TME.

Tumor microenvironment (TME) is the internal environment in which tumor cells survive, consisting of tumor cells, fibroblasts, endothelial cells, and immune cells, as well as non-cellular components, such as exosomes and cytokines. Exosomes are tiny extracellular vesicles (40-160nm) containing active substances, such as proteins, lipids and nucleic acids. Exosomes carry biologically active miRNAs to shuttle between tumor cells and TME, thereby affecting tumor development. Tumor-derived exosomal miRNAs induce matrix reprogramming in TME, creating a microenvironment that is conducive to tumor growth, metastasis, immune escape and chemotherapy resistance. In this review, we updated the role of exosomal miRNAs in the process of TME reshaping.

Neoplastic tissues are composed not only by tumor cells but also by several non-transformed stromal cells, such as cancer-associated fibroblasts, endothelial and immune cells, that actively participate to tumor progression. Starting from the very beginning of carcinogenesis, tumor cells, through the release of paracrine soluble factors and vesicles, i.e., exosomes, modify the behavior of the neighboring cells, so that they can give efficient support for cancer cell proliferation and spreading. A mandatory role in tumor progression has been recently acknowledged to metabolic deregulation. Beside undergoing a metabolic reprogramming coherent to their high proliferation rate, tumor cells also rewire the metabolic assets of their stromal cells, educating them to serve as nutrient donors. Hence, an alteration in the composition and in the flow rate of many nutrients within tumor microenvironment has been associated with malignancy progression. This review is focused on metabolic remodeling of the different cell populations within tumor microenvironment, dealing with reciprocal re-education through the symbiotic sharing of metabolites, behaving both as nutrients and as transcriptional regulators, describing their impact on tumor growth and metastasis.

Background Colorectal cancer is the second leading cause of cancer death. Almost half of the patients present recurrence within 5 years after the treatment of the primary tumor, the majority, with metastasis. On the other hand, in the search for new animal models that simulate metastatic cancer, it has been suggested that fibroblasts immersed in the peritumoral stroma (cancer-associated fibroblasts (CAFs)), play a relevant role in the development of cancer. The objective of this study was to identify an adequate animal model to study metastatic colon cancer and the application of new treatments. Methods Human CAFs and normal fibroblasts (NF) for transplant and culture were obtained from surgical fresh samples of patients with adenocarcinoma of sigmoid colon. Stromal cell purity was evaluated by morphology and immunostaining with vimentin (VIM) as a fibroblast marker and anti-proColXIα1 as a specific human CAF marker. Phenotypic characterization of cultured stromal cells was performed by co-staining with mesenchymal and epithelial cell markers. For identification in mice, human CAFs were labeled with the PKH26 red fluorescence dye. Cell line HT-29 was used as tumor cells. Transplant in the head of the pancreas of 34 SCID mice was performed in four different groups, as follows: I. 150,000 CAFS (n = 12), IIa. 1.5 million HT29 cells (n = 7), IIb. 150,000 NF+1.5 million HT29 cells (n = 5), III. 150,000 CAFS+1.5 million HT29 cells (n = 10). After euthanasia performed one month later, histological analysis was made using hematoxylin–eosin and anti-proColXIα1. A histopathological score system based on three features (tumor volume, desmoplasia and number of metastasized organs) was established to compare the tumor severity. Results The CAFs and NF cultured were proColXIα1+/VIM+, proColXIα1/alphaSMA+ and proColXIα1+/CK19+ in different proportions without differences among them, but the CAFs growth curve was significantly larger than that of the NF (p < 0.05). No tumor developed in those animals that only received CAFs. When comparing group II (a + b) vs. group III, both groups showed 100% hepatic metastases. Median hepatic nodules, tumor burden, lung metastases and severity score were bigger in group III vs group II (a + b), although without being significant, except in the case of the median tumor volume, that was significantly higher in group III (154.8 (76.9–563.2) mm3) vs group II (46.7 (3.7–239.6) mm3), p = 0.04. A correlation was observed between the size of the tumor developed in the pancreas and the metastatic tumor burden in the liver and with the severity score. Conclusion Our experiments demonstrate that cultured CAFs have a higher growth than NF and that when human CAFs are associated to human tumor cells, larger tumors with liver and lung metastases are generated than if only colon cancer cells with/without NF are transplanted. This emphasizes the importance of the tumor stroma, and especially the CAFs, in the development of cancer.

Background Cancer-associated fibroblasts (CAFs) are activated fibroblasts associated with cancer. They have an important role in tumor growth and metastasis. Artemisinin (ART) is a sesquiterpene lactone extracted from Chinese herb qinghao, and artemether (ARM), artesunate (ARS) and dihydroartemisinin (DHA) were synthesized derivatives of artemisinin, which also have anti-malarial and anti-cancer effects such as artemisinin. Methods In this study, we investigated the in-vitro and in-vivo effects of artemisinin derivatives on inactivating cancer-associated fibroblasts and uncovered its underlying mechanism. Results We demonstrated that ARS and DHA could revert L-929-CAFs and CAFs from activated to inactivated state in vitro. Mechanically, ARS and DHA could suppress TGF-β signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF-β signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo. Conclusions Artemisinin derivatives are potential therapeutic agents for the treatment of breast cancer.

Purpose: The aim of this study is to investigate the differential expression of α-sma-positive fibroblasts (CAFs) in nasopharyngeal carcinomas (NPCs), nasopharyngitis, metastatic tissues of NPCs and its prognostic value in NPCs. Methods: The expression of α-sma-labeled CAFs in 85 NPCs, 32 nasopharyngitis and 12 metastatic tissues of NPCs was detected by immunohistochemical method. The relationship between CAFs and clinicopathological parameters of NPCs was analyzed. Results: The high density of CAFs in the NPCs, nasopharyngitis and metastatic tissues of NPCs group were 41.2% (35/85), 6.2% (2/32) and 83.3% (10/12), and a significant difference was showed among these three groups (P0.05), but closely correlated with T stage and relapse (P

Background: Liver is one of the most preferred destinations of distant metastasis in gastric cancer (GC). As effective treatment is still limited, the prognosis of GC patients bearing liver metastasis is poor. We filter out lysyl oxidase (LOX) to study its function in the tumor microenvironment (TME) and seek for potential therapeutic targets. Methods: Transcription analysis on 6 cases of liver metastasis of GC patients with respective paired primary tumors and adjacent normal livers was performed. The filtration out of LOX was done using 5 datasets. 69 GC liver metastasis tissues were utilized to perform immunohistochemistry (IHC) and analyze prognosis. Computed Tomography (CT) combined 3D organ reconstruction bioluminescence imaging was performed to precisely evaluate the metastatic tumor burden on liver of intrasplenic injection mouse model. Human and mouse cancer associated fibroblasts (CAFs) in liver metastasis were separated to culture to study the interaction of LOX and TGF-β1. Patients-derived xenograft (PDX) model was established using liver metastasis of patients to evaluate the therapeutic value of LOX inhibitor β‐aminopropionitrile (BAPN). Results: CAFs-derived LOX at liver metastatic niche of GC promotes niche formation and outgrowth thus predicts poor prognosis. Meanwhile tumor cells in niche secrete TGF-β1 to nourish CAFs and stimulate them to produce more LOX in turn. The mechanism involved in LOX-mediated proliferation facilitation is enhancement of Warburg effect. The inhibitor of LOX, BPAN could hamper the effect brought by LOX in vivo and in vitro. Interpretation: Our study has unveiled a positive feedback loop between CAFs and tumor cells in liver metastasis niche of GC. The core molecule is LOX which facilitates Warburg effect. Targeting LOX with its inhibitor BAPN might serve as a potential therapeutic strategy. Fund: This research was supported by the National Natural Science Foundation of China (31872740), the 100-member plan of the Shanghai Municipal Commission of Health and Family Planning (2017BR043), Shanghai Science and Technology Commission Project(17ZR1416800), Renji Hospital Training Fund (PYMDT-003, PYIII-17–015), National Natural Science Foundation of China (81672358), the Shanghai Municipal Education Commission—Gao feng Clinical MedicineGrant Support (20181708), Program of Shanghai Academic/Technology Research Leader(19XD1403400), Science and Technology Commission of Shanghai Municipality (18410721000), Shanghai Municipal Health Bureau (2018BR32), China Postdoctoral Science Foundation (2018M640403), National Natural Science Foundation of China (81701945) and Youth project of Shanghai Municipal Health Commission(20164Y0045). Keywords: Gastric cancer, Liver metastasis, LOX, CAFs, Warburg effect

Although the mechanisms underlying the genesis and progression of breast cancer are better understood than ever, it is still the most frequent malignant tumor in women and one of the leading causes of cancer death. Therefore, we need to establish new approaches that lead us to better understand the prognosis of this heterogeneous systemic disease and to propose new therapeutic strategies. Cancer is not only a malignant transformation of the epithelial cells merely based on their autonomous or acquired proliferative capacity. Today, data support the concept of cancer as an ecosystem based on a cellular sociology, with diverse components and complex interactions between them. Among the different cell types that make up the stroma, which have a relevant role in the dynamics of tumor/stromal cell interactions, the main ones are cancer associated fibroblasts, endothelial cells, immune cells and mesenchymal stromal cells. Several factors expressed by the stroma of breast carcinomas are associated with the development of metastasis, such as matrix metalloproteases, their tissular inhibitors or some of their regulators like integrins, cytokines or toll-like receptors. Based on the expression of these factors, two types of breast cancer stroma can be proposed with significantly different influence on the prognosis of patients. In addition, there is evidence about the existence of bi-directional signals between cancer cells and tumor stroma cells with prognostic implications, suggesting new therapeutic strategies in breast cancer.

Cancer associated fibroblasts (CAFs) play a main role in breast cancer progression and metastasis. Estrogens modulate in breast CAFs the expression of microRNAs (miRNAs) that are involved in the development of many tumors. In order to provide novel insights on the regulation of miRNAs by estrogens in breast cancer, we analyzed the expression of 754 miRNAs in CAFs obtained from primary mammary tumors and CAFs derived from a cutaneous breast cancer metastasis. Using the TaqMan&trade, Human MicroRNA Array, we found that 17&beta, estradiol (E2) modulates numerous peculiar and common miRNAs in CAFs derived from primary and the metastatic malignancies. In particular, we assessed that E2 modulates 133 miRNAs (41 up and 92 downregulated) in CAFs derived from primary breast tumors, whereas E2 modulates 415 miRNAs (399 up and 16 downregulated) in CAFs derived from a cutaneous metastasis of breast carcinoma. Therefore, a number of miRNAs three times higher in metastatic CAFs with respect to primary breast CAFs was found modulated by E2. Our findings shed new light on the cumulative regulation of miRNAs by E2 in the main players of the tumor microenvironment as CAFs. Moreover, our data may be taken into consideration that is useful toward innovative prognostic and therapeutic approaches in breast cancer progression.

// Zongyuan Yang 1, * , Sen Xu 1, * , Ping Jin 1 , Xin Yang 1 , Xiaoting Li 1 , Dongyi Wan 1 , Taoran Zhang 1 , Sixiang Long 1 , Xiao Wei 1 , Gang Chen 1 , Li Meng 1 , Dan Liu 1 , Yong Fang 1 , Pingbo Chen 1 , Ding Ma 1 , Qinglei Gao 1 1 Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China * These authors have contributed equally to this work Correspondence to: Ding Ma, email: dma@tjh.tjmu.edu.cn Qinglei Gao, email: qlgao@tjh.tjmu.edu.cn Keywords: ovarian cancer, CAFs, MARCKS, senescence, Twist1 Received: January 07, 2016 Accepted: March 28, 2016 Published: April 13, 2016 ABSTRACT The Cancer Genome Atlas network has revealed that the ‘mesenchymal’ epithelial ovarian cancer (EOC) subtype represents the poorest outcome, indicating a crucial role of stromal cancer-associated fibroblasts (CAFs) in disease progression. The cooperative role of CAFs in EOC metastasis has long been recognized, but the mechanisms of stromal CAFs activation are still obscure. Therefore, we carried out an integrative analysis to identify the regulator genes that are responsible for CAFs activation in microdissected tumor stroma profiles. Here, we determined that myristoylated alanine-rich C-kinase substrate (MARCKS) was highly expressed in ovarian stroma, and was required for the differentiation and tumor promoting function of CAFs. Suppression of MARCKS resulted in the loss of CAF features, and diminished role of CAFs in supporting tumor cell growth in 3D organotypic cultures and in murine xenograft model. Mechanistically, we found that MARCKS maintained CAF activation through suppression of cellular senescence and activation of the AKT/Twist1 signaling. Moreover, high MARCKS expression was associated with poor patient survival in EOC. Collectively, our findings identify the potential of MARCKS inhibition as a novel stroma-oriented therapy in EOC.

Colon cancer, the second leading cause of cancer-related deaths in the world, is usually diagnosed in invasive stages. The interactions between cancer cells and cells located in their niche remain the crucial mechanism inducing tumor metastasis. The most important among those cells are cancer-associated fibroblasts (CAFs), the heterogeneous group of myofibroblasts transdifferentiated from numerous cells of different origin, including endothelium. The endothelial-to-mesenchymal transition (EndMT) is associated with modulation of cellular morphology, polarization and migration ability as a result of microtubule cytoskeleton reorganization. Here we reveal, for the first time, that invasive colon cancer cells regulate EndMT of endothelium via tubulin-&beta, 3 upregulation and its phosphorylation. Thus, we concluded that therapies based on inhibition of tubulin-&beta, 3 expression or phosphorylation, or blocking tubulin-&beta, 3&rsquo, s recruitment to the microtubules, together with anti-inflammatory chemotherapeutics, are promising means to treat advanced stages of colon cancer.

The tumor microenvironment has been suggested to participate in tumorigenesis, but the nature of the communication between cancer cells and the microenvironment, especially in response to anticancer drugs, remains obscure. We determined that activation of the CCAAT/enhancer binding protein delta (CEBPD) response to Cisplatin and 5-Fluorouracil in cancer-associated macrophages and fibroblasts contributed to the metastasis, invasion, acquired chemoresistance and stemness of cancer cells by in vitro and in vivo assays. Specifically, reporter and in vivo DNA binding assays were used to determine that Pentraxin 3 (PTX3) is a CEBPD responsive gene and serves a protumor role upon anticancer drug treatment. Finally, a PTX3 peptide inhibitor RI37 was developed and assessed the antitumor effects by in vivo assays. RI37 could function as a promising inhibitor for preventing cancer progression and the metastasis, invasion and progression of drug-resistant cancers. The identification of PTX3 provided a new insight in the interaction between host and tumor and the RI37 peptide showed a great opportunity to largely reduce the risk of invasion and metastasis of cancer and drug-resistant cancers.

Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and therapeutic resistance. A strict dependency between BCSCs and stromal cell components of tumor microenvironment exists. Thus, novel therapeutic strategies aimed to target the crosstalk between activated microenvironment and BCSCs have the potential to improve clinical outcome. Here, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using patient-derived samples (n = 16) and breast cancer cell lines, and determined the potential benefit of targeting leptin signaling in these model systems. Conditioned media (CM) from cancer-associated fibroblasts and breast adipocytes significantly increased mammosphere formation in breast cancer cells and depletion of leptin from CM completely abrogated this effect. Mammosphere cultures exhibited increased leptin receptor (OBR) expression and leptin exposure enhanced mammosphere formation. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology among mammospheres treated with CM and leptin. Interestingly, leptin increased mammosphere formation in metastatic breast cancers and expression of OBR as well as HSP90, a target of leptin signaling, were directly correlated with mammosphere formation in metastatic samples (r = 0.68/p = 0.05; r = 0.71/p = 0.036, respectively). Kaplan-Meier survival curves indicated that OBR and HSP90 expression were associated with reduced overall survival in breast cancer patients (HR = 1.9/p = 0.022; HR = 2.2/p = 0.00017, respectively). Furthermore, blocking leptin signaling by using a full leptin receptor antagonist significantly reduced mammosphere formation in breast cancer cell lines and patient-derived samples. Our results suggest that leptin/leptin receptor signaling may represent a potential therapeutic target that can block the stromal-tumor interactions driving BCSC-mediated disease progression.

Maintenance of both normal epithelial tissues and their malignant counterparts is supported by the host tissue stroma. The tumor stroma mainly consists of the basement membrane, fibroblasts, extracellular matrix, immune cells, and vasculature. Although most host cells in the stroma possess certain tumor-suppressing abilities, the stroma will change during malignancy and eventually promote growth, invasion, and metastasis. Stromal changes at the invasion front include the appearance of carcinoma-associated fibroblasts (CAFs). CAFs constitute a major portion of the reactive tumor stroma and play a crucial role in tumor progression. The main precursors of CAFs are normal fibroblasts, and the transdifferentiation of fibroblasts to CAFs is driven to a great extent by cancer-derived cytokines such as transforming growth factor-β. During recent years, the crosstalk between the cancer cells and the tumor stroma, highly responsible for the progression of tumors and their metastasis, has been increasingly unveiled. A better understanding of the host stroma contribution to cancer progression will increase our knowledge about the growth promoting signaling pathways and hopefully lead to novel therapeutic interventions targeting the tumor stroma. This review reports novel data on the essential crosstalk between cancer cells and cells of the tumor stroma, with an emphasis on the role played by CAFs. Furthermore, it presents recent literature on relevant tumor stroma- and CAF-related research in non-small cell lung cancer.