Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
Despite successive advances in clinical diagnosis and therapeutic intervention, cancer-associated morbidity and mortality keeps up with escalating cost to human society. Clinicians are confronted with an unprecedented challenge in curing cancers with de novo or acquired resistance. Failure to achieve effective and long-lasting treatment effects arises from the complexity of malignancies, particularly when plasticity of cancer cells is coupled with survival adaptability conferred by the pathologically co-opted stroma in the tumor microenvironment (TME). Targeting immune checkpoints, such as programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA4), provide significant benefit in multiple tumor types and produce substantial anticancer responses. Tissue resident stromal cells, although damaged together with cancer cells upon cytotoxic treatments, represent an ever-replenishing source that contributes to tumor restoration from residual cancer cells in the post-therapy stage. The TME displays a continually changing landscape, generating significant impacts on treatment outcome in clinics. Moving forward, implementing patient-specific analysis in clinical oncology with TME-oriented agents will significantly improve the specificity and efficacy of targeted therapies, thereby accelerating the translation of novel conceptions and groundbreaking discoveries in the TME biology through multiple bench-to-bed pipelines in current settings of precision cancer medicine.
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiaotong University School of Medicine, Shanghai, China
Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
Department of Medicine and VAPSHCS, University of Washington, Seattle, WA, USA
Paul Chiao
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiaotong University School of Medicine, Shanghai, China
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
*Address all correspondence to: sunyu@sibs.ac.cn
1. Introduction
Tumor development implicates the coevolution of transformed cells and the surrounding TME. In solid organs, the TME comprises extracellular matrix, neovasculature and multiple stromal cell types, conferring neoplastic cells multiple capabilities including sustained growth, elevated migration, accelerated invasion, promoted drug resistance and more importantly, enhanced metastasis [1]. In contrast to cancer cells, stromal components in the TME are generally stable in genetics and represent a potentially ideal target for therapeutic intervention.
There is accelerated progress in both the design and application of anticancer therapies. However, to date, most clinical regimens including chemotherapy, radiation and targeted therapy fail to cure patients, even with the integration of cutting-edge techniques and facilities. The case is, cancers that show overt initial responses to treatments frequently relapse as resistant malignancies, and pathological relapse remains as a major challenge in clinical oncology. Tumor outgrowth and disease exacerbation relies on not only genetic modifications in somatic cells but also fitness advantages of such mutations provide within the TME. It is increasingly evident that heterologous cell lineages within the TME actively alter therapeutic response and shape cancer resistance [2]. The distinct TME attributes within a given tumor select for mutations that allow survival, expansion and repopulation of cancer cells, while significantly creating tumor heterogeneity. Such a plasticity promotes the development of drug resistance through several mechanisms, including mutations of the target genes, reactivation of the targeted pathways, and cancer cross talk with the surrounding TME, with the latter largely overlooked in the past decades [3]. Besides, mounting data support that stromal cells, either naïve or therapeutically damaged, can produce and secrete a large group of soluble factors into the TME milieu, which act as critical signals delivered in a paracrine fashion and dramatically confer therapeutic resistance on cancer cells. Therefore, the TME is biologically active in the course of disease progression and exerts pathological impacts in a spatiotemporally volatile manner, underscoring the necessity of considering the TME as a dynamic entity in designing novel agents and developing therapeutic strategies. In this chapter, we propose to offer a body of essential information that delivers an updated account of the newly emerging TME biology, provide a significant guide to the most recent literature, and envision prospects for future research in basic, translational and clinical medicine.
In the microenvironment of healthy tissues, the stroma functions as a physical barrier against tumorigenesis. Nevertheless, cells transformed by intrinsic or extrinsic events can make major changes that stimulate the adjacent microenvironment to support disease progression. Such changes include remodeling of extracellular matrix (ECM), recruitment of fibroblasts, chemoattraction of immune cells, migration of neuroendocrine cells and networking of endothelial cells (vascularization). How do the genetic and/or epigenetic variations present within cancer cells generate a phenotypically complicated TME, which further exert profound influences on tumor development? The differences in selective pressures of in vivo conditions, such as local acidity, intermittent hypoxia and growth factor production within a tumor can actively shape the pathway of disease progression. Besides all the autonomous factors generated by the tumor itself, distinct environmental landscapes within the tumor foci select for mutations that engender increased malignancy, foster tumor heterogeneity and enhance therapeutic resistance, all factors closely correlated with decreased treatment efficacy and increased clinical failure.
As cancer cells expand at a given site and generate early insults that form the initial tumor niches, host-resident benign cell types coevolve with the neoplastic cells in the same tissue, both populations are continuously engaged in aging-related pathologies (Figure 1).
Figure 1.
Schematic outline of cell type components within a typical TME. Although intercellular interactions confer various malignant potentials on cancer cells in the tumor foci, soluble factors released from cell subpopulations can actively suppress the local immune/inflammatory activities, thereby creating an inhibitory and hostile environmental niche for infiltrating cells recruited into the tumor from other sites. EGF, epidermal growth factor; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor-1; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; TGF-β, tumor growth factor-β; VEGF, vascular endothelial growth factor; IL, interleukin; MCP-1, monocytic chemotactic protein 1; SDF-1, stroma-derived factor 1; CCL3, chemokine C-C motif ligand 1; CXCL12, chemokine C-X-C motif 12.
2.1.1. Cancer-associated fibroblasts
Fibroblasts represent an abundant and predominant cell type that maintains the structural framework in the connective tissue of solid organs. Normal fibroblasts typically suppress tumor formation; however, cancer-associated fibroblasts (CAFs), to the contrary, mainly promote tumorigenesis and facilitate metastasis. Compared with their normal counterparts, CAFs exhibit increased proliferation, enhanced ECM production, accumulated basement membrane deposition, strengthened cytokine synthesis and secretion including hepatocyte growth factor (HGF), multiple interleukins (ILs), platelet-derived growth factor (PDGF), stromal cell-derived factor 1 (SDF1), tumor growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) [4]. Alternatively, other mesenchyme-derived cell types, such as adipocytes, can also contribute to tumor growth and disease progression. For instance, adiponectin from the differentiated adipocytes increases VEGF-A expression in human chondrosarcoma cells through adiponectin receptor (AdipoR), hypoxia-inducible factor-1α (HIF)-1α, phosphoinositide 3 kinase (PI3K), Akt and mammalian target of rapamycin (mTOR) signaling cascades [5].
There are debates on the origin of CAFs during cancer progression. Some data suggest that CAFs are derived from the endothelial-to-mesenchymal transition, whereas other studies support that epithelial-to-mesenchymal transition (EMT) is responsible for CAF production [6, 7].
CAFs accumulated in the TME are subject to activation by cytokines and growth factors present in the nearby niches, such as fibroblast growth factor (FGF), monocyte chemotactic protein 1 (MCP1), PDGF, TGF-β and secreted proteases [8, 9]. Once activated, CAFs release pro-inflammatory factors to activate the nuclear factor (NF)-KB signaling in transformed cells, a typical cell-cell cross talk that significantly promotes tumorigenesis [10]. In addition, CAFs in the mammary TME select for bone-specific metastatic traits in primary tumor cells, partially based on the mutual interaction between Src+ breast cancer cells and CAFs that produce chemokine C-X-C motif ligand 12 (CXCL12) and insulin-like growth factor 1 (IGF1) [11]. A recent study suggested that circulating CAFs (cCAFs) with co-expressed fibroblast-associated protein (FAP) and α-smooth muscle actin (α-SMA) are distinguishable in the peripheral blood of patients with metastatic breast cancer. Furthermore, both cCAFs and circulating tumor cells (CTCs) are of significantly higher number in the metastatic group than in the localized breast cancer group, implying that cCAFs may complement CTCs as a clinically specific biomarker in metastatic breast cancer [12]. This also consolidates that functional roles of CAFs in tumor progression involve malignant activities not only in the primary foci but also in the systemic delivery of cancer cells of high metastatic potential to colonize in a foreign microenvironments, further supporting the interactions between cancer and TME in both the local and distant niches.
2.1.2. Neovasculature
Development of the tumor-associated vascular network is dynamic and dramatically influences tumor behaviors. Starting from regional angiogenesis, vascular networks are strengthened by co-opting mature vessels within the tissue, recruiting endothelial precursors from bone marrow. Specifically, neovascularization involves degradation and reconstruction of existing vascular basement membranes in a tissue-specific manner, as it evidenced by the fact that concurrent targeting of VEGF and Angiopoietin-2 (Ang2) potentiates the effectiveness of VEGF inhibition and prevents basement membrane destruction [13]. It is likely that newly co-opted vessels sustain certain properties of the original tissue, which exerts critical influences on the resulting vascular network.
However, deficient tumor vasculature such as unbalanced vessel development results in formation of hypoxic microenvironments with limited nutrient supplementation. Spatial interval from vascular beds to tumor foci creates a local gradient, a crucial factor for the distribution of anticancer agents within a given tumor tissue. In clinics, angiogenesis is assessed by microvessel density (MVD), an important prognostic factor for clinical outcomes of multiple tumor types. In prostate cancer, CD105-MVD reflects the angiogenic conditions in patients treated with neoadjuvant hormonal therapy (NHT) and acts as an emerging independent predictor of biochemical recurrence in prostate cancer patients after radical prostatectomy with NHT [14]. In addition, upregulation of pro-angiogenic ligand VEGFA is associated with a worse prognosis in metastatic colorectal, lung and renal cell cancers. For example, high VEGF expression was subsequently correlated with a short overall survival rate for colorectal cancer patients exhibiting lymph node metastasis [15].
2.1.3. Immune system
Upon disease progression, both the innate and adaptive immune systems are implicated in tumor-associated activities. Despite the ability of the immune system to mount antitumor responses, immune suppression mechanisms, however, often prevent such a process. Particularly, T-cell activation engages both positive and negative checkpoint signals to finely tune responses to avoid overt damage and autoimmunity. Particularly, cancer immunoediting is a process by which the immune system can paradoxically restrain or facilitate cancer progression [16]. The interaction between tumor and immune system is now regarded as a crucial factor relevant for the clinical management of cancer patients [17].
2.1.3.1. Checkpoint-associated immunosuppression
Blockade of immune checkpoints including cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has achieved significant benefits in multiple cancer types by minimizing inhibitory signals while amplifying effective antitumor responses. Anti-CTLA4, PD-1 or PD-L1 administration as mono-immunotherapy have demonstrated clinical activity in more than 15 cancer types, including bladder carcinoma, Hodgkin lymphoma, melanoma, non-small cell lung carcinoma (NSCLC) and renal cell carcinoma (RCC) [18]. Although immune-based regimens for cancer treatment are expected to increase substantially within the next years, combinatorial inhibition of PD-1 and CTLA4 holds the potential to further enhance antitumor efficacy. Clinical efficacy of the combination of ipilimumab and nivolumab in the setting of malignant melanoma at advanced stage is recently witnessed, and successfully passed approval by the FDA for the treatment of patients with unresectable or metastatic melanoma harboring wild-type BRAFV600 [19].
Thus, clinical data support that antitumor immunity is operative even in the most advanced cancer stages, and multiple immunosuppressive pathways are active in the TME which need to be co-targeted to release the full effector function of tumor-associated immune cells [20]. In fact, diverse additional immunomodulatory pathways and suppressive factors produced or secreted by stromal cells in the TME can be exploited as useful targets for immune checkpoint targeting [21]. However, some critical questions still remain open. For example, which combinations should move toward practical development? What type of patients will benefit most from such therapies? Systematic consideration of these issues by determining the leading drug targets expressed by cancer cells will allow substantial enhancement of the immune responses to eradicate the disease.
Representative immunotherapeutic targets currently in clinical or preclinical pipelines.
BTLA, B and T lymphocyte attenuator; BTNL2, butyrophilin-like protein 2; CSF1R, macrophage colony-stimulating factor receptor 1; CTLA4, cytotoxic T lymphocyte antigen 4; CXCL12, chemokine (C-X-C motif) ligand 12; CXCR4, C-X-C chemokine receptor type 4; GITR, glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein; HHLA2, HERV-H LTR-associating protein 2; HVEM, herpes virus entry mediator; ICOS, inducible T cell co-stimulator; IDO, indoleamine 2,3-dioxygenase; IGSF, immunoglobulin superfamily; ILT, immunoglobulin-like transcript; KIR, killer inhibitory immunoglobulin-like receptor; LAG3, lymphocyte activation gene 3 protein; LIR, leukocyte immunoglobulin-like; LTA, lymphotoxin-α; MIC, MHC class I polypeptide-related sequence; PD1, programmed cell death protein 1; PDL1, programmed cell death 1 ligand 1; PVR, poliovirus receptor; SIRPA, signal-regulatory protein- alpha; TGF-β, transforming growth factor-β; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domains; TIM3, T cell immunoglobulin mucin 3; TL1A, TNF-like ligand 1A; TMIGD2, transmembrane and immunoglobulin domain-containing protein 2; TNFRSF25, TNFR superfamily member 25; TNFR, TNF receptor; VEGF, vascular endothelial growth factor; VISTA, V-domain immunoglobulin suppressor of T cell activation.
*Plerixafor (Mozobil; Genzyme/Sanofi) is approved by the US Food and Drug Administration not as an antitumor therapy but as a bone marrow mobilizing agent for bone marrow transplantation including autologous cases. However, it is currently in clinical trials of chronic lymphocytic leukemia, multiple myeloma and non-Hodgkin''s lymphoma patients.
Contents of Table 1 adapted from Mahoney et al. [25] with permission from Nature Reviews Drug Discovery, copyright 2015.
Concurrent inhibition of PD-1 and CTLA4 significantly increases response rate in melanoma patients and is now in Phase III trials in multiple cancer types [19, 22]. Since immunosuppression is dominant, it makes sense that a standard immunotherapy begins with immune checkpoint blockade instead of a direct immune stimulation. Release from immunosuppression will allow for combination with multiple immunotherapies that eventually activate the immune response. Results from the Phase I trial of synergistic CTLA4 and PD-1 blockade suggest that such a combination is clinically effective, but highly toxic to patients [19]. In this case, alternative combinations with the anti–PD-1 pathway backbone will likely produce better response in cancer clinics with fewer side effects. A group of immunological pathway candidates for combinatorial inhibition of the immune checkpoint is in various stages of clinical trials (Table 1). The corresponding agents are designed to directly stimulate cytotoxic T cells, block immunosuppressive factors, inhibit regulatory T cells (Treg) functions, interfere with the natural killer cell inhibitory activities or abolish the effects of soluble factors produced by stromal cells.
2.1.3.1.1. Tumor-associated macrophages (TAMs)
In solid tumors, TAMs compose 5–40% of the tumor mass and are usually correlated with poor prognosis. Distinct from M1-macrophages, the immune cell subpopulation of pro-inflammatory and anti-cancer properties, M2-macrophages are immunosuppressive, contributing to the matrix-remodeling and favor tumor progression [23]. TAMs are either tissue-resident or derived from peripheral sites including the bone marrow (BM) and spleen. Increasing lines of evidence suggest an active role for TAMs in supporting multiple malignant behaviors such as invasiveness at the leading edge of tumors. Particularly, studies have demonstrated that TAMs promote cancer cell invasion through a paracrine signaling loop involving tumor-associated granulocyte macrophage colony stimulating factor (GM-CSF) and macrophage-derived epidermal growth factor (EGF) in breast cancer and glioma [24, 25]. Additionally, the close vicinity of cancer cells in epithelial-mesenchymal transition (EMT) and TAMs at the invasive tumor front implies that these two cell type may mutually interact with each other. Beyond the leading edge, TAMs represent a major source of proteases including cysteine cathepsins, which promote tumor progression and therapeutic resistance in multiple cancer types [26].
However, it remains so far unclear how macrophages switch from tumor suppressing to tumor promoting upon disease progression. It is likely that environmental factors such as tumor hypoxia are involved in such a transition. Specifically, TAMs accumulate at sites of hypoxia in growing tumors, and their recruitment is mediated by macrophage chemoattractants such as endothelin-2 and VEGF [27]. Recent data further suggest that coexistence of hypoxia and free fatty acids (FFAs) exacerbates macrophage-mediated inflammation [28]. As noteworthy, TAM accumulation in these regions enhances angiogenesis and subsequent acquisition of invasive phenotype, supporting that the initial hypoxic response in growing tumors may induce a phenotypic switch of macrophages, which is correlated with their changed polarization [29].
2.1.3.1.2. Myeloid-derived suppressor cells (MDSCs) and Treg cells
In a typical TME, immunosuppressive effects may also be exerted by myeloid-derived suppressor cells (MDSCs), which result from aberrant myelopoiesis that occurs in developing tumors [30]. Functionally identified as an immunosuppressive subpopulation, MDSCs are immature myeloid cells that sustain normal tissue homeostasis upon stimulation of the host by various systemic insults such as viral infection and traumatic stress [31]. However, MDSCs dramatically promote tumor growth by supporting angiogenesis, cancer cell survival, tumor metastases and pre-metastatic niche formation [32]. In particular, the process of tumorigenesis can mobilize MDSCs which subsequently infiltrate developing tumors and promote local vascularization and disrupt routine immunosurveillance, including dendritic cell (DC) antigen presentation, M1 macrophage polarization, T cell activation and natural killer (NK) cell cytotoxicity blockade [33]. Depletion of MDSCs in animal models with neutralizing antibodies markedly reduced metastasis, further consolidating that MDSCs promote tumor progression [31]. Furthermore, cancer patients display elevated numbers of peripheral MDSCs, which is positively associated with the disease aggravation extent and therapeutic failure rate [34]. Interestingly, monocytic MDSCs can be reprogrammed to exhibit an antitumorigenic phenotype upon bacteria-elicited activation of the immune system in animal models [35]. In such a case, increased T helper type 1 (TH1) cytokines, decreased T cell-inhibitory factors and differentiation of MDSCs toward M1-like macrophages were observed, suggesting that immunotherapies are able to subvert autonomous responses of MDSCs to extrinsic stimuli to maintain homeostasis, an exploitable aspect of such an immune cell subgroup in cancer treatment.
Phenotypically, Treg cells represent another TME cell type with multiple immune modulatory functions in human cancer patients. As an essential part of the normal tissue under physiological conditions, Treg cells control the proliferation and activation of adaptive immune system including T and B cells, thus having a critical role in homeostasis maintenance. However, Treg cells can generate diverse effects on tumorigenesis. For example, increased numbers of Treg cells are correlated with poor survival of several pathologies including lung, colorectal and estrogen receptor (ER)-negative breast cancer; however, their role on prostate and ER-positive breast tumor development remains uncertain [36]. Similar to MDSCs, Treg cells prevent tumor-associated antigen presentation and suppress cytotoxic T cell function by blocking the release of cytolytic granules [37].
In nature, tumor-associated Treg cells have heterogeneous phenotypes, and they may accumulate through various mechanisms including peripheral recruitment, TME-based proliferation or progenitor-initiated differentiation upon stimulation by tumor-secreted factors [38]. Thus, CD25 antibody-involved Treg-targeting or other treatment regimens may promote immunotherapy responses, like agents designed for MDSCs [39].
2.1.3.1.3. Other stromal cell types implicated in tumor progression
Several stromal cell types recently emerged with the potential to generate remarkable influences on human cancer. Particularly, adipocytes and their progenitors in obese populations promote tumorigenesis across a handful of obesity-related cancer types [40, 41]. Adipocytes cause the enrichment of prostate cancer stem cells (CSCs) through a distinct cycle of autocrine amplification, suggesting a novel mechanism underlying the mutual interaction between adipocytes and prostate CSCs [42]. Moreover, adipose cells can be recruited to growing tumor foci, differentiating into pericytes and incorporating into vessel walls [43]. In both the basement membrane (BM) and local environment of solid tumors, atypical stem-promoting functions of nerves can enhance the aggressiveness of cancer cells, including those in gastrointestinal, pancreatic and prostate tumors [44–46]. Furthermore, inflammation associated with the gut microbiome is considered as one of the major contributing factor of colorectal cancer outcomes. The US National Institutes of Health has recently launched an initiation to thorough study the human microbiome in various anatomical sites including the gut [47]. Targeting agents with anti-inflammatory (such as aspirin) or antimicrobial efficacy can prevent colorectal cancer tumorigenesis, thereby elongating patient survival [48]. Given the emergence of non-classical stromal cell types in solid tumors, creative combination anticancer therapies are being continually developed in the industrial pipelines and will show promising benefits in mitigating disease progression.
2.1.4. Tumor-associated exosomes
Diverse signaling activities within the TME involve autocrine and/or paracrine signaling loops of cytokines, chemokines and growth factors. Besides such a typical aspect, exosome-based shedding has recently emerged as an alternative modality of cell-cell communication. In particular, tumor-derived exosomes from the primary site reprogram the surrounding TME to form a pro-tumorigenic niche, orchestrating BM-derived progenitors to facilitate metastatic dissemination [49]. A recent study demonstrated that tumor-associated exosomes express unique integrins and determine organotropic metastasis through creating pre-metastatic niches via integrin-mediated fusion with organ-specific resident cells [50]. Aggressive melanoma-derived exosomes increase tumor metastasis rates and programs BMDCs at the pre-metastatic sites to form a proangiogenic phenotype [51]. More importantly, multiple stromal cell types can release exosomes, as exemplified by fibroblast-secreted exosomes which promote cell migration through WNT-PCP signaling in breast cancer [52]. In such a case, NK cell-derived exosomes from human blood harbor proteins to induce the tumor cytotoxicity and activate immune cells ex vivo. Conversely, new data demonstrated that endometrial cancer cells transmit small regulatory RNAs to endometrial fibroblasts through exosomes, suggesting a reciprocal mode of intercellular communication between cancer cells and related fibroblasts in human tumors [53]. Distinct prostate cancer (PCa) cell populations release exosomes that contain miRNAs to modify the local or premetastatic niche, and such miRNAs have different patterns between PCa bulk and CSCs exosomes that function collaboratively in tumor progression and metastasis [54]. The most abundant exosomes-related miRNAs thus can be regarded as potentially significant biomarkers and therapeutic targets in clinical oncology.
2.2. The therapeutically remodeled TME alters clinical outcome
Recent studies have recognized benign or noncancerous cells of the TME are major determinants of treatment efficacy in a large number of preclinical and clinical cases, an important mechanism of acquired resistance that is beyond the intrinsic characteristics of cancer cells but use to be masked by the de novo resistance of malignancies. Insightful appreciation of mechanisms involved in regulation of drug tolerance is crucial for improved cancer treatment. Specifically, host resident cells of the TME actively modulate tumor responses to chemotherapy and targeted therapies through production of secreted factors [55].
Neoadjuvant or conventional chemotherapy-induced DNA damage can cause WNT16B overexpression, a phenomenon found in the TME of prostate, breast and ovarian cancer patients. Upon genotoxic insults, NF-κB acts as a key signaling node that actively mediates WNT16B production. Cell-based experiments and tumor transplant models demonstrated the protective effect of fibroblast-derived WNT16B, indicating that WNT16B secreted by stroma attenuates cancer cell apoptosis induced by genotoxicity, and counteracts drug response through activation of a DNA damage secretory program (DDSP) [56–59] (Figure 2). The study presents new opportunities for future advanced treatments that rationally integrate agents to confine the TME activities. For instance, depleting stroma-derived WNT16B, which would specifically overcome such a “new” but not “minor” TME-associated resistance mechanism [57, 60]. As supporting evidence, CAFs are similarly enriched in colorectal cancer (CRC) during the post-therapy stage and display enhanced cytokine IL-17A, which helps maintain the tumor infiltrating cells (TICs) through activation of NF-κB signaling [61].
Besides overturning traditional law of nature that anticancer treatments mainly restrain cancer cells, the discovery raises the novel appreciation that genotoxic regimens including chemotherapy and radiation indeed activate the stroma to promote disease resistance, an important advancement corroborated by several other concurrent but mutually independent reports of breast cancer models that strongly imply DNA damage-elicited alterations of the TME as an pathological entity that eventually minimizes the overall therapeutic response [62, 63]. The BM is enriched with cells of varying progeny beyond myeloid cell populations that are mobilized and recruited to the TME in response to treatments. Importantly, BM-derived mesenchymal stem cells (BMMSCs) can secrete polyunsaturated fatty acids, chemoprotective factors that favor cancer cell survival [64]. Although the data showed that only the cisplatin-involving therapy can induce such a change, the TME-derived fatty acids eventually conferred resistance to multiple agents even at a systemic level. Alternatively, therapeutic evasion by cancer propagating cells (CPC) represents a major obstacle in leukemia clinics. Recent data showed that the BM niche is created by acute lymphoblastic leukemia (ALL) cells following cytarabine and daunorubicin treatment [65]. Mesenchymal cells recruited by leukemia cell-derived CCL3 can build a therapy-induced shelter and evolve from Nestin+ cells to a smooth muscle actin (a-SMA)+ cells under TGF-β influence, ultimately developing into fiber residues. Formation of such an early protective niche significantly contributes to the failure of therapeutic intervention by preventing complete remission.
Cocultured fibroblasts regulate the in vitro sensitivity of head and neck squamous cell carcinoma (HNSCC) to epithelial growth factor receptor (EGFR) antibodies or matrix metalloproteinase (MMP) inhibitors [66]. Furthermore, tumor-stroma cross talk plays a crucial role in the acquisition of lung cancer resistance to EGFR-tyrosine kinase inhibitors (TKIs) through activating the c-Met/PI3K/Akt pathway in vitro and in vivo, implying such an interaction may be therapeutically targeted for lung cancer patients with EGFR-activating mutations [67]. HGF represents one of the major stroma-released soluble regulators of lung cancer sensitivity, whereas gefitinib in synergy with anti-HGF antibody or the HGF antagonist NK4 showed decent efficacy in abolishing fibroblast-induced EGFR-TKI resistance. Similarly, co-inhibition of EGFR and c-Met signaling with a novel bi-specific EGFR/c-Met antibody effectively blocked malignant development including resistance additively compared with the single-agent treatments [68].
Figure 2.
WNT16B is significantly produced upon genotoxic damage to human stromal cells and promotes therapeutic resistance to surviving cancer cells. (A) Genome-wide expression pattern of normal human primary prostate stromal cells. Heatmap depicts the relative mRNA abundance after exposure of cells to typical DNA damaging agents (H2O2, hydrogen peroxide; Bleo, bleomycin; Rad, ionizing radiation). (B) Top list of upregulated human genes annotated as extracellular or secreted factors, with average expression fold change ≥3.5 by comparison of post-treatment vs. pretreatment samples. Note, WNT16B shows up among the overexpressed genes, with outstanding expression fold change. (C) Working model for cancer cell non-autonomous therapeutic resistance acquired from the TME upon genotoxic treatments including chemotherapy and radiation. Therapeutic agents cause apoptosis in subsets of cancer cells by eliciting a DNA damage response (DDR), while cancer cells with DDR deficiency (DDR-insensitive, or DDR-) may escape from such insults. Simultaneously, senescence is induced in stromal cells adjacent to epithelial cells surrounding the gland, with a secretory phenotype DDSP developed after DDR events. A persistently activated signaling network is triggered by the DNA strand breaks. The DDSP is usually characterized by a spectrum of autocrine- and paracrine-acting proteins. The soluble factors reinforce the senescent phenotype in damaged cells, enhance cancer cell repopulation, with increased occurrence of tumor relapse and distant metastasis. A handful of co-synthesized factors including WNT16B and SPINK1 holds the potential to serve as both a serum biomarker to determine treatment index and a therapeutic target to minimize the TME-conferred therapeutic resistance. DDR, DNA damage response; ECM, extracellular matrix; TME, tumor microenvironment. Color images of (A) adapted from Xu et al. with permission from Trends in Cancer, copyright 2016.
The development and maintenance of vasculature is regulated by diverse pathways, including those engaging proangiogenic factors produced by both the tumor and stroma [69]. Upon genotoxic treatments, stromal expression of VEGF and other angiogenic factors including angiopoietin 1 (ANGPT1) and angiopoietin-like 4 (ANGPTL4) is enhanced, potentially contributing to vasculature development within the therapeutically damaged TME [56, 70]. Expression of the secreted frizzled-related protein 2 (SFRP2), a typical modulator of Wnt signaling, is increased in the stroma damaged by the chemotherapeutic cycles [56]. Beyond holding the potential to promote angiogenesis via the calcineurin/NFAT signaling in a non-canonical Wnt pathway [71, 72], SFRP2 can interact directly with WNT16B to enhance its canonical activities, eventually generating a substantially strengthened malignant phenotype including remarkable drug resistance in prostate cancer [73]. Data from targeting angiopoietins (Ang1, Ang2, Ang4) which cause CAF accumulation and neoangiogenesis in the TME, and TEK (referring to Tie1/Tie2) receptors responsible for the maturation and plasticity of blood vessels, are recently reported [74, 75]. Inhibiting angiogenesis in patients to overcome one of the side effects caused by cytotoxic agents is thus a novel strategy to block neoplastic growth and deprive cancer of acquired resistance.
Increasing lines of evidence support that the TME is critical for the development of chemoresistance through multiple mechanisms including drug distribution regulation and inflammatory response control. Particularly, the infiltration of myeloid-derived cells is increased in human breast cancer post-chemotherapy, with the cellular composition as a strong clinical predictor of overall survival [63]. Furthermore, myeloid cell-derived MMP9 influences both vascular leakage and response to chemotherapeutic drugs including doxorubicin. Therefore, tumor response to classical chemotherapeutic agents can be improved by targeting the TME with chemicals or antibodies that modify MMP activity and/or chemokine signaling. In another perspective, cancer treatments currently applied as the mainstay of clinical oncology indeed represent a double-edged sword, which is frequently compromised in reality by a therapeutically remodeled TME. The structural change, and more importantly, the functional modification of such a TME, casts a critical step toward development of more advanced malignancies including but not limited to the phenotypic switch via EMT, generation of circulating tumor cells (CTCs), local invasion in primary foci and metastasis to distant organs [76].
2.3. Development of targeting strategies in precision medicine
While the functional constituents of the TME generate profound impacts on disease progression and minimize the efficacy of anticancer therapies, experimental data indicate that such alterations are indeed exploitable and can open new avenues to develop advanced strategies and design innovative cancer regimens.
To date, there are a few leading research groups that have made progress in the TME biology by generating relevant databases and presenting therapeutic opportunities to prevent TME-induced cancer resistance. First of all, cytokines, growth factors and survival-associated proteins released by the TME are straightforward and valid therapeutic targets. As an efficient growth stimulator, IL-6 enhances resistance by counteracting chemotherapy and hormone therapy of multiple myeloma; it is also a therapeutic target in Castleman’s disease and several epithelial malignancies including mammary, breast ovarian, prostate cancers [77]. Recent data demonstrated that HGF is a critical TME determinant of resistance to BRAF inhibitors, setting the baseline for combinations of HGF-targeting monoclonal antibodies and RTK inhibitors that dampen the receptor c-Met activation [78, 79]. Identification of the distinct role of stroma-derived WNT16B in prostate cancer strongly supports translational studies in cancer therapy, as evidenced by the pilot preclinical trial integrating a monoclonal WNT16B antibody and routine chemotherapy to treat prostate tumors [73]. It is tempting to compare the efficacy of WNT16B-implicated pathway blockade and a wider suppression of the TME response to genotoxicity by inactivating the NF-κB complex. As the NF-κB activity differs between various stromal cell lineages upon therapeutic insults, it would be necessary to compare the effects of NF-κB suppression in individual TME-derived cell types. Nevertheless, there are caveats when selecting NF-κB as a general therapeutic target, although accumulating experimental data have established the NF-κB complex as a key regulator of inflammation and a driver of cancer progression. However, reverse but convincing data proved that activated NF-κB components enhance the sensitivity of cancer cells to chemicals that induce apoptosis and senescence, a special mechanism that controls tumorigenesis [80, 81]. As a supporting point, canonical NF-κB is found to be a Fas transcription activator, though the alternative NF-κB acts as a Fas transcription repressor [82]. In such a case, NF-κB promotes Fas-mediated cancer cell apoptosis, while suppression of NF-κB may abolish the Fas-initiated cell death and interfere with tumor regression achieved by the host immune system.
Strategies to inhibit the cancer resistance acquired from the TME in the course of either chemotherapy or targeted therapy have the value to improve overall therapeutic outcome. Generally, the TME exerts pathological influence on cancer cell survival as an early stage, while subsequent repopulation frequently occurs via the activation of signaling networks that elicit a typical secretory phenotype and/or tumor-stroma cross talk. To date, an array of agents are developed to minimize these activities, particularly small molecule inhibitors against key signal pathway nodes including the ATM/ATR-associated DDR repair machinery, p38MAPK cascade, mTOR subunits, JAK/STAT axis, NF-κB complex and CCAAT/enhancer binding protein (C/EBP) components. Alternatively, cytostatic antibodies with the ability to neutralize major soluble factors of significant roles in shaping advanced cancer phenotypes, such as those targeting MMPs, IL-6, IL-8, WNT16B, SFRP2, SPINK1 and AREG are also strong candidates that can be exploited to target the TME [57]. Fortunately, a handful of agents successfully acquired FDA approval for the systemic intervention of cancer patients while many others are in the industrial pipelines or clinical trials. As scientific acumen, an optimal therapeutic strategy is to consider the cancer a systemic disease at diagnosis and to pursue combinational therapy that incorporate cytotoxic agents and feasible cytostatic drugs either concurrently or sequentially, the latter actually more preferred [83]. Continued efforts in future will consolidate preclinical studies with novel therapeutics that deprive cancer of TME-conferred resistance, which is administered synergistically with cancer-targeting agents in pathological conditions that implicate a stress-responsive and functionally active TME.
Recently achieved in-depth profiling of cancer mutations by deep sequencing has enabled appreciation of the importance of tumor neoantigens in the immune surveillance of cancer, with the dream of “personalized immunotherapy” now realized. In particular, conceptual developments in cancer biology have caused a paradigm shift in the perspective we look at the TME when taking account of the immune system and its interaction with cancer. A simple but useful pragmatic framework allowing to stratify the TME into four classes according to the presence or absence of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression was raised [84]. The proportion of tumors categorized as type I (~38%) and type II (~41%) by this framework is high in melanoma, and type I TME-harboring patients have the best prognosis and highest likelihood to respond to anti–PD-1/PD-L1 agents [85, 86]. Some malignancies such as prostate and pancreatic cancers, however, may not contain a high proportion of type I TME; in such a case, anti–PD-1/PD-L1 monotherapies are not expected to be highly effective [87]. Therefore, it is important to clarify which aspects of cancer immunity need to be targeted by novel immunotherapies, with the aim to provide benefit for patients with non-type I TME tumors. Different types of therapeutic interventions may need to be combined to generate a strong antitumor response, by effectively engaging immunity to suppress specific types of TME [17].
To treat various types of cancer-immune microenvironments, anti–PD-1 and anti–PD-L1 drugs will probably set the baseline of many future treatments for cancer, whereas the opportunities to combine these agents with surgery, radiation, immunogenic chemotherapy and targeted therapy and in class I tumors can be easily foreseen. The alternative strategy of chimeric antigen receptor T (CAR-T)-cell immunotherapy is essentially a combination treatment in nature. Providing earlier combination therapies to cancer patients, it is likely that approximately 50% or more of cancer types particularly some solid tumors such as melanoma and renal cell carcinoma are effectively prevented or controlled
Traditional anticancer treatments with cytotoxic drugs have generated limited promotion in the cure rates of various malignancies. Chemotherapy, radiation and targeted therapy, however, still have a large place in cancer clinics. Using novel approaches derived from the development of systems medicine, we will have a more thorough and accurate understanding of human cancer complexity and will be able to stratify patients appropriately. Personalized medicine has the potential to bring the best outcome for cancer patients, while healthcare costs should be made affordable and, most importantly, the combination therapies must be designed in a safe, rational, and effective way.
The fast moving research areas have undoubtedly set the stage for future investigation on interactions between cancer cells and the surrounding shelter, the TME. Development of methods for high content profiling of this complex biological landscape, and the other side, advancement of therapeutic strategies to overcome the pathological problem at a systemic level, thus turns out to be a very important task for prospective research and clinical practice.
The authors apologize to investigators whose work is not cited due to space limitations. They thank Dr. Peter Nelson (Fred Hutchinson Cancer Research Center, USA) and Dr. Judith Campisi (Buch Institute for Research on Aging, USA) for kindly providing fibroblast cell lines and conferring critical comments. This work is supported by a US DoD PCRP Idea Development Award (PC111703), National Natural Science Foundation of China (81472709) and the National 1000 Youth Elites Research Program of China to YS.
Fibroblast-activating protein or fibroblast-associated protein
FGF
Fibroblast growth factor
FSP1
Fibroblast-specific protein 1
GM-CSF
Granulocyte macrophage colony-stimulating factor
HGF
Hepatocyte growth factor
HIF1α
Hypoxia-inducible factor 1α
HNSCC
Head and neck squamous cell carcinoma
hTERT
Human telomerase reverse transcriptase
IGF-1
Insulin growth factor 1
IL
Interleukin
MAPK
Mitogen-activated protein kinase
MCP1
Monocyte chemotactic protein 1
MDR
Multiple drug resistance
MDSC
Myeloid-derived suppressor cell
MMP
Matrix metalloproteinase
MRD
Minimal residue disease
mTOR
Mammalian target of rapamycin
MVD
Microvessel density
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells
NHT
Neoadjuvant hormonal therapy
NK
Natural killer
NSCLC
Non-small cell lung cancer
PCa
Prostate cancer
PDGF
Platelet-derived growth factor
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PI3K
Phosphoinositide 3 kinase
RCC
Renal cell carcinoma
RTK
Receptor tyrosine kinase
SCLC
Small-cell lung cancer
SDF-1
Stromal cell-derived growth factor 1
SFRP2
Secreted frizzled-related protein 2
TAM
Tumor-associated macrophage
TGF-β
Transforming growth factor-β
TH1
T helper type 1
TIC
Tumor-infiltrating cell
TIL
Tumor-infiltrating lymphocyte
TKI
Tyrosine kinase inhibitor
TME
Tumor microenvironment
TNBC
Triple-negative breast cancer
TNF
Tumor necrosis factor
Treg
Regulatory T cell
uPAR
Urokinase plasminogen activator receptor
Vegf
Vascular endothelial growth factor
References
1.Gu L, Mooney DJ. Biomaterials and emerging anticancer therapeutics: engineering the microenvironment. Nature Reviews Cancer. 2016;16:56–66.
2.Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501:346–354.
3.Ramos P, Bentires-Alj M. Mechanism-based cancer therapy: resistance to therapy, therapy for resistance. Oncogene. 2015;34:3617–3626.
4.Polanska UM, Orimo A. Carcinoma-associated fibroblasts: Non-neoplastic tumour-promoting mesenchymal cells. Journal of Cellular Physiology. 2013;228:1651–1657.
5.Lee HP, Lin CY, Shih JS, Fong YC, Wang SW, Li TM, et al. Adiponectin promotes VEGF-A-dependent angiogenesis in human chondrosarcoma through PI3K, Akt, mTOR, and HIF-α pathway. Oncotarget. 2015;6:36746–36761.
6.Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Research. 2007;67:10123–10128.
7.Orr B, Riddick AC, Stewart GD, Anderson RA, Franco OE, Hayward SW, et al. Identification of stromally expressed molecules in the prostate by tag-profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate. Oncogene. 2012;31:1130–1142.
8.Dumont N, Liu B, Defilippis RA, Chang H, Rabban JT, Karnezis AN, et al. Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia. 2013;15:249–262.
9.Marsh T, Pietras K, McAllister SS. Fibroblasts as architects of cancer pathogenesis. BBA-Molecular Basis of Disease. 2013;1832:1070–1078.
10.Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell. 2010;17:135–147.
11.Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, et al. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell. 2013;154:1060–1073.
12.Ao Z, Shah SH, Machlin LM, Parajuli R, Miller PC, Rawal S, et al. Identification of cancer-associated fibroblasts in circulating blood from patients with metastatic breast cancer. Cancer Research. 2015;75:4681–4687.
13.Coutelle O, Schiffmann LM, Liwschitz M, Brunold M, Goede V, Hallek M, et al. Dual targeting of Angiopoetin-2 and VEGF potentiates effective vascular normalisation without inducing empty basement membrane sleeves in xenograft tumours. British Journal of Cancer. 2015;112:495–503.
14.Miyata Y, Mitsunari K, Asai A, Takehara K, Mochizuki Y, Sakai H. Pathological significance and prognostic role of microvessel density, evaluated using CD31, CD34, and CD105 in prostate cancer patients after radical prostatectomy with neoadjuvant therapy. The Prostate. 2015;75:84–91.
15.Kimura Y, Morohashi S, Yoshizawa T, Suzuki T, Morohashi H, Sakamoto Y, et al. Clinicopathological significance of vascular endothelial growth factor, thymidine phosphorylase and microvessel density in colorectal cancer. Molecular Medicine Reports. 2016;13:1551–1557.
16.Teng MW, Galon J, Fridman WH, Smyth MJ. From mice to humans: developments in cancer immunoediting. The Journal of Clinical Investigation. 2015;125:3338–3346.
17.Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nature Reviews Clinical Oncology. 2016;13:143–158.
18.Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56–61.
19.Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. The New England Journal of Medicine. 2013;369:122–133.
20.Melero I, Berman DM, Aznar MA, Korman AJ, Perez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nature Reviews Cancer. 2015;15:457–472.
21.Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nature Reviews Drug Discovery. 2015;14:561–584.
22.Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. The New England Journal of Medicine. 2015;372:2006–2017.
23.Sousa S, Brion R, Lintunen M, Kronqvist P, Sandholm J, Monkkonen J, et al. Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Research. 2015;17:101.
24.Coniglio SJ, Eugenin E, Dobrenis K, Stanley ER, West BL, Symons MH, et al. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Molecular Medicine. 2012;18:519–527.
25.Su SC, Liu Q, Chen JQ, Chen JN, Chen F, He CH, et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell. 2014;25:605–620.
26.Shree T. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes & Development. 2011;25:2465–2479.
27.Lewis C, Murdoch C. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. The American Journal of Pathology. 2005;167:627–635.
28.Snodgrass RG, Boss M, Zezina E, Weigert A, Dehne N, Fleming I, et al. Hypoxia potentiates palmitate-induced pro-inflammatory activation of primary human macrophages. The Journal of Biological Chemistry. 2015;291:413–424.
29.Escribese MM, Casas M, Corbi AL. Influence of low oxygen tensions on macrophage polarization. Immunobiology. 2012;217:1233–1240.
30.Gabrilovich D, Nefedova Y. ROR1C regulates differentiation of myeloid-derived suppressor cells. Cancer Cell. 2015;28:147–149.
31.Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nature Reviews Cancer. 2013;13:739–752.
32.Condamine T, Ramachandran I, Youn JI, Gabrilovich DI. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annual Review of Medicine. 2015;66:97–110.
33.Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nature Medicine. 2013;19:1423–1437.
34.Arina A, Bronte V. Myeloid-derived suppressor cell impact on endogenous and adoptively transferred T cells. Current Opinion in Immunology. 2015;33:120–125.
35.Shirota Y, Shirota H, Klinman DM. Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells. The Journal of Immunology. 2012;188:1592–1599.
36.Barth SD, Schulze JJ, Kuhn T, Raschke E, Husing A, Johnson T, et al. Treg-Mediated immune tolerance and the risk of solid cancers: findings from EPIC-Heidelberg. Journal of the National Cancer Institute. 2015;107:djv224.
37.von Boehmer H, Daniel C. Therapeutic opportunities for manipulating T(Reg) cells in autoimmunity and cancer. Nature Reviews Drug Discovery. 2013;12:51–63.
38.Blatner NR, Mulcahy MF, Dennis KL, Scholtens D, Bentrem DJ, Phillips JD, et al. Expression of RORgammat marks a pathogenic regulatory T cell subset in human colon cancer. Science Translational Medicine. 2012;4:164ra59.
39.Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nature Reviews Immunology. 2012;12:253–268.
40.Tsoli M, Swarbrick MM, Robertson GR. Lipolytic and thermogenic depletion of adipose tissue in cancer cachexia. In Seminars in Cell & Developmental Biology. 2016;54:68–81.
41.Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Medicine. 2011;17:1498–1503.
42.Tang KD, Liu J, Jovanovic L, An J, Hill MM, Vela I, et al. Adipocytes promote prostate cancer stem cell self-renewal through amplification of the cholecystokinin autocrine loop. Oncotarget. 2015;7:4939–4948.
43.Zhang Y, Daquinag AC, Amaya-Manzanares F, Sirin O, Tseng C, Kolonin MG. Stromal progenitor cells from endogenous adipose tissue contribute to pericytes and adipocytes that populate the tumor microenvironment. Cancer Research. 2012;72:5198–5208.
44.Demir IE, Friess H, Ceyhan GO. Nerve-cancer interactions in the stromal biology of pancreatic cancer. Frontiers in Physiology. 2012;3:97.
45.Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, et al. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341:1236361.
46.Ferdousi M, Azmi S, Petropoulos IN, Fadavi H, Ponirakis G, Marshall A, et al. Corneal confocal microscopy detects small fibre neuropathy in patients with upper gastrointestinal cancer and nerve regeneration in chemotherapy induced peripheral neuropathy. PloS One. 2015;10:e0139394.
47.Green ED, Watson JD, Collins FS. Human genome project: Twenty-five years of big biology. Nature. 2015;526:29–31.
48.Liao XY, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. New England Journal of Medicine. 2012;367:1596–1606.
49.Barcellos-Hoff MH, Lyden D, Wang TC. The evolution of the cancer niche during multistage carcinogenesis. Nature Reviews Cancer. 2013;13:511–518.
50.Liu Y, Cao X. Organotropic metastasis: role of tumor exosomes. Cell Research. 2016;26;149–150.
51.Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Medicine. 2012;18:883–891.
52.Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151:1542–1556.
53.Maida Y, Takakura M, Nishiuchi T, Yoshimoto T, Kyo S. Exosomal transfer of functional small RNAs mediates cancer-stroma communication in human endometrium. Cancer Medicine. 2015;5:304–314.
54.Sánchez CA, Andahur EI, Valenzuela R, Castellón EA, Fullá JA, Ramos CG, et al. Exosomes from bulk and stem cells from human prostate cancer have a differential microRNA content that contributes cooperatively over local and pre-metastatic niche. Oncotarget. 2015;7:3993–4008.
55.Ostman A. The tumor microenvironment controls drug sensitivity. Nature Medicine. 2012;18:1332–1334.
56.Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nature Medicine. 2012;18:1359–1368.
57.Chen F, Qi X, Qian M, Dai Y, Sun Y. Tackling the tumor microenvironment: what challenge does it pose to anticancer therapies? Protein & Cell. 2014;5:816–826.
58.Sun Y. Tumor microenvironment and cancer therapy resistance. Cancer Letters. 2016;380:205–215.
59.Xu Q, Chiao P, Sun Y. Amphiregulin in cancer: new insights for translational medicine. Trends in Cancer. 2016;2:111–113.
60.Sun Y, Nelson PS. Molecular pathways: involving microenvironment damage responses in cancer therapy resistance. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2012;18:4019–4025.
61.Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. The Journal of Experimental Medicine. 2013;210:2851–2872.
62.Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell. 2012;150:165–178.
63.Nakasone ES, Askautrud HA, Kees T, Park JH, Plaks V, Ewald AJ, et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell. 2012;21:488–503.
64.Roodhart JML, Daenen LGM, Stigter ECA, Prins HJ, Gerrits J, Houthuijzen JM, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell. 2011;20:370–383.
65.Duan CW, Shi J, Chen J, Wang B, Yu YH, Qin X, et al. Leukemia propagating cells rebuild an evolving niche in response to therapy. Cancer Cell. 2014;25:778–793.
66.Johansson AC, Ansell A, Jerhammar F, Lindh MB, Grenman R, Munck-Wikland E, et al. Cancer-associated fibroblasts induce matrix metalloproteinase-mediated cetuximab resistance in head and neck squamous cell carcinoma cells. Molecular Cancer Research: MCR. 2012;10:1158–1168.
67.Wang W, Li Q, Yamada T, Matsumoto K, Matsumoto I, Oda M, et al. Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clinical Cancer Research. 2009;15:6630–6638.
68.Castoldi R, Ecker V, Wiehle L, Majety M, Busl-Schuller R, Asmussen M, et al. A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity. Oncogene. 2013;32:5593–5601.
69.Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends in Molecular Medicine. 2011;17:347–362.
70.Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology. 2008;6:2853–2868.
71.Courtwright A, Siamakpour-Reihani S, Arbiser JL, Banet N, Hilliard E, Fried L, et al. Secreted frizzle-related protein 2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway. Cancer Research. 2009;69:4621–4628.
72.Siamakpour-Reihani S, Caster J, Bandhu Nepal D, Courtwright A, Hilliard E, Usary J, et al. The role of calcineurin/NFAT in SFRP2 induced angiogenesis–a rationale for breast cancer treatment with the calcineurin inhibitor tacrolimus. PLoS One. 2011;6:e20412.
73.Sun Y, Zhu D, Chen F, Qian M, Wei H, Chen W, et al. SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment. Oncogene. 2016;35:4321–4334.
74.Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nature Reviews Molecular Cell Biology. 2009;10:165–177.
75.Brunckhorst MK, Xu Y, Lu R, Yu Q. Angiopoietins promote ovarian cancer progression by establishing a procancer microenvironment. The American Journal of Pathology. 2014;184:2285–2296.
76.Coppe JP, Boysen M, Sun CH, Wong BJ, Kang MK, Park NH, et al. A role for fibroblasts in mediating the effects of tobacco-induced epithelial cell growth and invasion. Molecular Cancer Research : MCR. 2008;6:1085–1098.
77.McMillin DW, Negri JM, Mitsiades CS. The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nature Reviews Drug Discovery. 2013;12:217–228.
78.Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du JY, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500–504.
79.Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 2012;487:505–509.
80.Jing H, Lee S. NF-kappaB in cellular senescence and cancer treatment. Molecules and Cells. 2014;37:189–195.
81.Fuchs D, Metzig M, Bickeboller M, Brandel C, Roth W. The Gbeta5 protein regulates sensitivity to TRAIL-induced cell death in colon carcinoma. Oncogene. 2015;34:2753–2763.
82.Liu F, Bardhan K, Yang D, Thangaraju M, Ganapathy V, Waller JL, et al. NF-kappaB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression. The Journal of Biological Chemistry. 2012;287:25530–25540.
83.Sun Y. Translational horizons in the tumor microenvironment: harnessing breakthroughs and targeting cures. Medicinal Research Reviews. 2015;35:408–436.
84.Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Research. 2015;75:2139–2145.
85.Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Science Translational Medicine. 2012;4:127ra37.
86.Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2014;20:5064–5074.
87.Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N, et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiology, Biomarkers & Prevention : A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2014;23:2965–2970.
Open access peer-reviewed chapter
