watch Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Oxford Academic. Google Scholar. Yun-Xin Lu. Dong-Liang Chen. Zhi-Xiang Zuo. Ze-Xian Liu. Qi-Nian Wu. Hai-Yu Mo. Zi-Xian Wang. De-Shen Wang. Heng-Ying Pu. Zhao-Lei Zeng. Bo Li. Dan Xie. Peng Huang. Mien-Chie Hung. Paul J Chiao. Rui-Hua Xu.
Authors contributed equally to this work. Cite Citation. Permissions Icon Permissions. Abstract Background. Figure 1. Open in new tab Download slide. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. Colorectal Cancer.
Cancer: Disease Control Priorities. Volume 3. Incidence trends and age distribution of colorectal cancer by subsite in Guangzhou, Search ADS. Aberrant cancer metabolism in epithelial-mesenchymal transition and cancer metastasis: mechanisms in cancer progression. Regulation of the Nampt-mediated NAD salvage pathway and its therapeutic implications in pancreatic cancer.
Mutant Kras- and pregulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma. Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through the redox modulation. IL-6 is a to kDa pleiotropic cytokine that is produced by various types of cells, including immune cells, fibroblasts, and certain tumor cells [ 13 , 16 , 17 ].
An alternative to classic-signaling has recently been described, termed trans-signaling, in which a complex is formed between IL-6 and a soluble form of IL-6R, sIL-6R, which then joining with membrane gp to generate downstream signaling events [ 19 ] Figure 1. Classic-signaling is limited to a few cell types since membrane IL-6R is only expressed on hepatocytes and immune cells. IL-6 plays an important role in immune responses and repair processes through classic-signaling, and may be involved in the pathogenesis of inflammatory diseases and cancers through trans-signaling.
However, the full range of biological functions of IL-6 mediated by classic and trans-signaling remains to be elucidated [ 23 ]. Emerging evidence shows that IL-6 plays critical roles in cancer development, progression and metastasis by regulating the tumor microenvironment and cancer stem cells [ 7 ]. In this review, we evaluate the evidence regarding potential use of IL-6 antagonists for breast cancer therapy and prevention. Figure 1: Action of IL-6 on target cells via classic-signaling and trans-signaling. Increasing evidence supports the notion that high levels of serum IL-6 are associated with poor prognosis, advanced disease, and metastases in breast cancer patients [ 6 , 13 , 25 - 28 ].
The three breast cancer subtypes rely on IL-6 signaling to varying degrees. Patients with above average serum levels of sIL-6R are more likely to experience recurrence compared to patients with lower levels of sIL-6R [ 32 ]. IL-6 treatment of the estrogen receptor-expressing cell line, MCF-7, showed a Notch-3 dependent up-regulation of the Notch ligand, Jagged-1, and the carbonic anhydrase IX [ 33 ].
IL-6 also promoted a hypoxia-resistant and invasive phenotype in MCF-7 cells [ 33 ]. Drug resistance is a critical problem in breast cancer therapy, and autocrine production of IL-6 by breast tumor cells promotes resistance to multi-drug chemotherapy [ 37 ]. Very recently, IL-6 has been suggested as a major factor influencing resistance to trastuzumab, a therapeutic HER2 antibody, in breast cancer [ 38 ]. Trastuzumab resistance in HER2-overexpressing breast cancer cells is shown to be mediated by the IL-6 inflammatory loop, leading to expansion of the breast cancer stem cell population [ 38 ].
Blockade of this IL-6 loop by an IL-6 antagonist, tocilizumab, reduced the cancer stem cell population, resulting in decreased tumor growth and metastasis in mouse xenografts [ 38 ]. Further studies are warranted to assess the potential of utilization of HER2 therapies in combination with IL-6 therapies to overcome drug resistance in HER2-positive breast cancers.
In comparison to other breast subtypes, triple-negative breast cancer cell lines secret the highest levels of IL-6 [ 40 ]. Triple negative breast cancers rely on the autocrine expression of IL-6 for growth [ 40 ]. Studies have shown that inhibition of IL-6 expression by shRNA in triple-negative breast cancer cells can lead to the suppression of colony formation and decreased cell survival in vitro as well as decreased tumor engraftment and growth in vivo [ 40 ].
With limited therapy options for aggressive triple-negative breast cancer, IL-6 signaling inhibitors may offer an important new therapeutic option. IL-6 signaling not only exerts its effects on breast cancer cells, but can also play a role in the surrounding tumor microenvironment, indirectly impacting cancer growth and progression [ 42 ]. The tumor microenvironment is composed of various cell types including mesenchymal stem cells, adipocytes, tumor-associated fibroblasts, endothelial cells, and immune cells, all of which are capable of interaction with tumor cells via cytokine networks [ 43 ].
Both autocrine and paracrine actions of IL-6 in the tumor microenvironment are reported to be critical for breast oncogenesis [ 6 , 43 ]. IL-6 produced by tissue-specific fibroblasts promotes the growth and invasion of breast cancer cells through STAT3-dependent up-regulation of Notch-3, Jagged-1, and carbonic anhydrase IX [ 44 , 45 ].
STAT3 phosphorylation in breast epithelial cells can be stimulated by paracrine signaling through IL-6 from both breast cancer cells and fibroblasts [ 46 ]. IL-6 secreted from senescent mesenchymal stem cells can increase the proliferation and migration of breast cancer cells by induction of STAT3 phosphorylation [ 14 ].
Utilizing IL-6 signaling inhibitors to target the tumor microenvironment and indirectly block cancer cell growth could be effective in treating and preventing breast carcinogenesis. Recently developed IL-6 targeting agents include chimeric, humanized or human monoclonal antibodies mAbs , avimers, and small molecules Figure 2. References are provided in parenthesis.
Siltuximab has been shown to be potentially effective in the treatment of various cancers as a single agent or in combination with other anti-cancer drugs [ 48 - 56 ]. In preclinical studies, siltuximab inhibited IL-6—induced activation of ovarian cancer cells [ 49 ], inhibited IL-6—induced survival of advanced prostate cancer [ 57 ], suppressed lung cancer growth in mouse xenograft models [ 55 ], and enhanced melphalan cytotoxicity in a preclinical multiple myeloma model [ 51 ]. A case report showed that complete remission was achieved in a patient with relapsed refractory multiple myeloma after single agent therapy with siltuximab [ 58 ].
The addition of siltuximab to bortezomib did not result in improved outcome in patients with relapsed or refractory multiple myeloma [ 59 ]. Lack of anti-multiple myeloma effect of siltuximab in clinical trials could be explained by emergence of ILindependent subclones or substitution for IL-6 by other IL-6 family cytokines that utilize gp as a shared signal transducer [ 60 ].
To date, no preclinical or clinical data are available for breast cancer therapy; however, the safety and efficacy profile of siltuximab is well established, making it ideal for future studies. Sirukumab, a human anti—IL-6 mAb, has been found to bind to human IL-6 with high affinity and specificity, and to suppress IL-6 activity. Pharmacokinetics PK , pharmacodynamics PD , and safety profile studies of sirukumab in healthy subjects have revealed good tolerability, desirable PK characteristics, and low immunogenicity [ 61 ]. Sirukumab has been studied in patients with rheumatoid arthritis RA , systemic lupus erythematosus SLE , and cutaneous lupus erythematosus [ 13 ].
Clinical efficacy of sirukumab was evaluated in a phase II study of patients with active RA failing methotrexate monotherapy and showed improvements in the symptoms of RA [ 62 ]. Sirukumab is a human mAb, and therefore it has an advantage of a very low immunogenicity in anti-cancer therapies. Crystal structure data have revealed that binding of olokizumab to site 3 the gp binding site on IL-6 induces a conformational change in IL-6 and neutralizes its biological activity by blocking receptor hexamer complex formation [ 63 ]. A phase I pharmacokinetic and safety study in healthy subjects was performed and showed no serious adverse events and rapid decreases in C-reactive protein concentration [ 64 ].
On the basis of the pathogenetic role of IL-6 in cancers, a study of the anti-cancer activity of olokizumab appears warranted. Given its inhibitory role against multiple myeloma, mAb may have potential activity against other types of cancer, including breast cancer. For cancer therapy, clazakizumab was evaluated for the treatment of non-small cell lung cancer NSCLC -related fatigue and cachexia and oral mucositis in patients with head and neck cancer [ 13 , 68 ].
In preclinical and clinical trials, clazakizumab ameliorated NSCLC-related anemia and cachexia [ 68 ]. No preclinical or clinical data are currently available for the activity of clazakizumab against breast cancer. PF has not been used clinically or preclinically for anti-cancer therapy. Thus far, no patients were reported to have severe adverse events. Avimers are created from a large family of human extracellular receptor domains by exon shuffling and phage display to generate multidomain proteins with binding properties that may overcome the limitations of mAbs [ 69 ].
C is composed of an IL-6—binding trimer and a IgG-binding domain, resulting in a heterotetrameric avimer with very high affinity for IL-6 and in vivo neutralizing activity.
Further studies are underway to identify the precise site of action of 6a. Molecular mechanism studies in breast cancer cell lines warrant further investigation of 6a as an anti-cancer therapeutic. Treatment with sgpFc significantly reduced colitis-associated premalignant cancer in mice [ 72 ]. Because of its specific blockade of proinflammatory trans-signaling [ 23 ], sgpFc has potential as an effective and safe therapeutic strategy for breast cancer. Anti-gp mAb and anti-gp chemical compounds bind to gp and inhibit ILinduced gp dimerization and signaling.
Generally, it has been shown that clinical efficacy as well as safety profiles among anti-IL-6 and anti-IL-6R mAbs appear similar in RA patients [ 73 ]. Currently available IL-6R blockers are discussed in this section and summarized in Table 1. MR, a rodent analog of tocilizumab, exhibited a dramatic effect on cachexia induced by an IL-6—overexpressing lung cancer [ 74 ].
MR inhibited fibrosarcoma growth in vivo [ 75 ]. Recent reports showed anti-cancer effects of tocilizumab in a colon cancer xenograft model [ 9 ] and the effects of combination therapy of tocilizumab and interferon-alpha against renal cell carcinoma [ 77 ]. Tocilizumab also inhibited tumor growth of trastuzumab resistant breast cancer cells [ 38 ].
However, so far no clinical study has been reported in breast cancer. The results of a phase II study to assess the safety and efficacy of sarilumab in active RA patients have been reported [ 73 ]. Sarilumab showed efficacy in patients with active RA compared to placebo [ 73 ]. For cancer therapy, inhibition of the growth of xenograft tumors of DU prostate , Calu3 lung , and A lung cells by sarilumab was reported both as a single agent and in combination with the VEGF blocker aflibercept [ 78 ].
The potential of sarilumab in cancer inhibition has been demonstrated, however, its effects in breast cancer are unknown and should be investigated. Its small size 26 kD should allow ALX to penetrate more effectively into tissues [ 79 ]. Injection of an adenovirus vector encoding NRI exhibited inhibitory effects on multiple myeloma cells S6B45 in vivo [ 80 ].
This study showed a sustained therapeutic concentration of NRI in the circulation and inhibitory activity comparable to that of the parent agent tocilizumab. SANT-7 showed activity against multiple myeloma in vitro and in vivo [ 82 , 83 ]. Combination therapy with SANT-7 and dexamethasone or all- trans -retinoic acid showed activity against multiple myeloma in a SCID-hu in vivo model and in cell lines [ 84 , 85 ].
The anti-differentiation potential of ERBF suggests that it could be utilized in anticancer therapies. Although increasing attention has recently been paid to the role of gp in cancer, no pharmaceutical company-driven anti-gp agents are currently under development. Anti-gp mouse mAbs and some chemical small molecules have been reported Figure 2. However, mouse mAbs are not eligible for human clinical studies and some small molecule inhibitors have not been studied in cancer.
Most recently, direct binding of a novel small molecule inhibitor to gp has been demonstrated [ 88 ]. B-R3 is a mouse mAb against gp that has been used in preclinical studies to inhibit gp signaling [ 22 , 89 ]. No clinical trials are underway with anti-gp mAbs yet. MDL-A binds to the extracellular domain of gp [ 92 ]. MDL-A analogues were synthesized and evaluated for their inhibitory activity against IL-6—dependent cell proliferation [ 93 ]. To date, no preclinical or clinical data are available for its activity against breast cancer.
SC is a small-molecule gp inhibitor that suppresses STAT3 signaling via induction of gp phosphorylation and down-regulation of gp glycosylation [ 94 ]. SC inhibited tumor growth of human ovarian cancer xenografts and reduced the number of tumor blood vessels [ 94 ]. Evidence of direct interaction between SC and gp was provided by drug affinity responsive target stability DARTS assay [ 94 ], and to date, no preclinical or clinical data are available for breast cancer therapy. The interaction of these drugs with gp was demonstrated indirectly via docking studies and a drug affinity responsive target stability assay.
To date, no clinical data are available for breast cancer therapy. Oral administration of LMT ameliorated collagen-induced arthritis and acute pancreatitis in mice. Lung tumours are characterized by extensive genomic aberrations including aneusomy, gains and losses of large chromosome regions, gene rearrangements, copy number gain, amplifications [ 17 ]. Genomic instability represents one of the hallmarks in human cancer resulting in various genetic aberrations at different level from mutations in single or few nucleotides to changes of part or entire chromosomes [ 18 ].
The term chromosomal instability CIN defines a type of genomic instability associated to numerical and structural variations of part or whole chromosomes, for example gain or loss of chromosome fragments, translocations, deletions and amplifications of DNA [ 19 , 20 ].
CIN could have clinical importance in lung cancer patients being generally associated with poor prognosis regardless of other conventional risk factors such as tumour stage, age and sex [ 21 - 23 ]. Furthermore, CIN may frequently generate the intertumor heterogeneity resulting in a possible increase, before the treatment, of resistant pre-existing sub-clones. Consistent with the selective pressure related to drug treatment, tumor cells characterized by hight levels of CIN might promote drug resistence [ 24 , 20 ].
Moreover, genomic diversity facilitates the adaptation of cancer cell populations in the context of tumor microenvironment resulting in tumor progression and poor prognosis [ 19 ]. Their results showed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations, particularly an elevated copy-number heterogeneity was associated with an increased risk of recurrence or death hazard ratio, 4. These finding demonstrate that intratumor heterogeneity due to CIN in NSCLC is strictly associated to increased risk of recurrence or death, suggesting its potential prognostic role [ 25 ].
Human malignancies are characterized by a high variable frequency of somatic mutations between and within tumor types, ranging from about 0. Lung cancer is featured by a high tumor mutational burden TMB compared to other cancer type, probably related to smoking habits frequently observed in lung cancer patients. Recent finding have highlighted the pivotal role of the TMB as predictor of response to immunotherapies [ 27 ].
The tumorigenesis in lung cancer represents a multi-step process involving genetic alterations. Previous studies proposed a mathematical modeling related to a clonal mutation burden in several cancer types, suggesting that lung cancer reflects predominantly mutations accumulated early during tumorigenesis compared to others cancers with late mutation rate [ 28 ]. Mutant allele specific imbalance MASI represents another genetic mechanism that could promote heterogeneity and impact tumorigenesis, progression, metastasis, prognosis and potentially therapeutic responses in cancer.
MASI could occur with copy neutral alteration defined as acquired uniparental disomy UPD , or with loss of heterozygosity LOH due to the loss of the wild-type allele [ 29 ].
Although intratumoral molecular heterogeneity in human cancer has historically attributed to genetic alterations, to date a high degree of heterogeneity has been related to epigenetic mechanisms, including DNA methylation, chromatin remodeling, and post-translational modification of histones [ 16 , 33 ]. Epigenetic modifications induce a variability in gene expression determining a remarkable diversity. Physiologically, a single miRNA can modulate cell growth, differentiation and apoptosis, therefore an altered expression of miRNAs in different cancer types can affect the deregulation of cellular activities [ 35 ].
Although preliminary results are encouraging, further prospective studies and clinical validation on large patient cohorts are needed in order to use these miRNAs as predictive biomarkers of the response to treatment to platinum-based chemotherapy in NSCLC patients. Beyond strictly genetic and epigenetic mechanisms, the heterogeneity could result from various non-genetic mechanisms, including the lung stem cell populations and the immune contexture of lung cancer [ 15 ].
CSCs represent a crucial non-genetic source of heterogeneity providing different subclonal lineages dynamically maintained in various solid tumors, including lung cancer [ 36 , 37 ]. Several studies showed that CSCs drive tumor formation and progression, metastasis, recurrence and drug resistance.
CSCs have unique characteristics including capacity of self-renewal, multipotency, ability to initiate new tumors in vivo, increased capacity of proliferation and differentiation [ 38 , 39 ]. Studies in genetically engineered mouse models have enabled to prove the existence of lung stem cells able to self-renew regenerating lung parenchima, bronchioles, alveoli and pulmonary vessels [ 40 ].
Moreover, the distinctive biology of pre-existing different lung cells could drive the distinct phenotypes and genotypes of tumors, resulting in heterogeneity since the tumor initiation. Historically, various lung stem cell populations in different anatomical sites lead to the development of different istotypes [ 41 ]. Increasing evidence has highlighted the key contribution of microenvironment in the initiation and progression of lung cancer, since cancer cells are closely interconnected with the milieu of the tumor.
The immune contexture of lung cancer is composed of several elements including endothelial cells, fibroblasts, myeloid cells, including T cells, B cells, natural killer cells, mature and immature dendritic cells, tumor-associated macrophages, neutrophils, and mast cells. Lung tumor heterogeneity could be caused by different acidity and oxygen conditions, or variable concentrations of growth factors that could generate different levels of selective pressure, which in turn could sustain the survival of some clones rather than others [ 42 ].
Furthermore, the microenvironment can affect drug resistance since a determinate tumor context could improve the formation of protective compartments in response to treatments. The variable pressure of lung tumor environment could generate inter- and intra-tumoral heterogeneity that affects sensitivity to target- and immuno- therapy response [ 44 ]. The different histotypes are associated with specific different mutational profiles Table 1 [ 46 - 73 ]. Technological advances in molecular biology have provided a comprehensive means of molecular profile and the identification of driver oncogenes.
Oncogenes generally encode proteins that regulate several cellular processes including proliferation and survival. NSCLC is one of the tumors with a higher mutation rate of protein-altering mutations, particularly adenocarcinomas showed a rate of 3. Large-scale sequencing studies have shown a broad spectrum of genetic aberrations in NSCLC and a different genetic profile between lung adenocarcinomas and lung squamous cell carcinomas [ 25 , 78 - 80 ].
NSCLC molecular profile is markedly distinct from other lung cancer histotypes: mainly in adenocarcinoma specific therapeutic targets have been defined. Beyond these targetable alterations, other genomic aberrations have been reported in adenocarcinoma, including mutations, copy number gene alterations, as well as fusion mechanisms involving the receptor tyrosine kinase, such as ROS1, NTRK1 and RET Table 1.
Historically, a better understanding of the genetic aberrations was confined exclusively to adenocarcinoma, but more recently next-generation sequencing technologies are allowing a better molecular characterization also in other hystotypes. Recently, increasing interest in comprehensive genome-wide characterization of SqCC has been reported, however, unfortunately no therapeutic targets have been yet identified. As it would be expected, molecular landscape in SqCC is distinct from the 'driver' mutations generally associated to adenocarcinoma.
Recently, Devarakonda and colleagues analysed the molecular profile of resected NSCLC specimens by sequencing a targeted panel consisting of 1, genes. The analyzed panel set of genes was selected based on knowledge of the most frequent genes involved in lung cancer pathogenesis, regardless of their clinical implications [ 27 ].
In conclusion, high heterogeneous genomic profiles between different histotypes of lung cancer could provide an explanation for great variable treatment response and prognostic stratification histotypes-related factors. Dietz and colleagues investigated the spatial distribution of allele frequencies of KRAS and EGFR mutations in lung adenocarcinomas throughout whole tumor sections in correlation to all different histopathological patterns. Heterogeneous distribution of EGFR mutations was observed within a primary tumor composed of mixed atypical adenomatous hyperplasia, bronchoalveolar carcinoma, and adenocarcinoma [ 89 ].
Previously, we demonstrated that homogeneity in EGFR aberrations occur within lung mixed ADCs regardless histological patterns, contrary to ALK rearrangements that are generally observed in solid patterns and exclusively in the adenocarcinoma areas of adenosquamous lung carcinomas [ 90 ]. In lung cancer, frequently cytologic samples or small biopsies represent the only specimens for tumor diagnosis and affect the choice of treatment, thus a potential genetic heterogeneity within a primary tumor could crucially affect clinical outcome to a specific treatment.
NSCLC patients harboring targetable driver mutations generally respond well to specific inhibitors, however some patients show short responses and TKIs resistance that could be frequently explained through molecular heterogeneity between the primary lung tumors and the metastases [ 91 - 93 ]. The intratumor genetic heterogeneity represents one of the most critical issues related to sensitivity to the treatment and ultimately to resistance to specific TKI. Moreover, numerous studies have revealed the concordance of EGFR status in primary tumours and corresponding metastases, suggesting a possible explanation of the discordance due to technical limitations [ 6 , 14 , 90 , , ].
In contrast, several results demonstrated hetereogeneity in the EGFR mutation status between the primary lung tumor and the metastases [ 94 , , ]. Chen et al analyzed EGFR mutational condition in paired samples of primary lung adenocarcinoma and regional lymph nodes or distant metastases.
Heterogeneity of EGFR mutations was higher rate of In conclusion, discordances between oncogenic driver mutations status in primary lesions and metastases may have significant implications in treatment with specific inhibitors of NSCLC patients. Tailored therapies based on the identification of molecular targets represent currently a well-established therapeutic scenario in the treatment of NSCLC patients, however short responses and development of resistance are frequently observed in daily clinical practice.
Patient-specific response and resistance can originate not only from secondary aberrations induced by targeted therapy but also from intratumoral genetic heterogeneity [ ]. To date, different models have been proposed to explain the difference of genetic profile between primary tumour and corresponding metastases. Particularly, a classical model for development of metastases proposes that primary tumor cells have a low metastatic potential, thus the acquirement of enough genetic aberrations improve the metastatic progression.
Another theory suggests a metastatic potential of primary tumor that leads a clonal progression from a non-malignant to malignant state, involving random metastases from tumor cells without any significant additional genetic aberrations [ ].
TRACERx analyzed the intratumor variability of several genetic aberrations including single or dinucleotide base substitutions, small insertions and deletions, somatic copy-number alterations [ 25 ]. Beyond heterogeneity of druggable driver mutations, previous studies have analyzed the presence of mutational signatures across human cancer types, proving that specific mutational signatures could correlate with defined tumors [ 26 ]. Recently, a multicenter prospective study analyzed the expression clonal and subclonal of these validated mutational signatures suggesting that the signature associated to APOBEC could frequently induce subclonal mutations resulting in a spatial heterogeneity [ 25 ].
In lung cancer, another great biological variability was reported between smokers versus never-smokers, since several carcinogens of the tobacco smoke lead to a high mutational rate including both driver and passenger mutations [ 26 , ]. Recently, Soo and colleagues showed the clinical-pathological features typical of never-smokers analyzed in a wide series of NSCLC, in order to clarify their characteristics still not fully known.
Genome-wide studies identified several potential genetic marker of susceptibility in LCINS, such as chromosomal locus 5p The biological differences between these two subsets result in differential response to therapies, including EGFR inhibitors, thus a better genetic characterization of lung cancer in non-smokers LCINS is needed [ ].
Discordance of molecular profiles between primary lesions and their corresponding metastases in the context of druggable driver mutations could be the key point in personalized medicine of lung cancer patients. Indeed, intra-tumor molecular heterogeneity represents a great source of concern in mixed tumor responses to treatment, including treatment with specific TKI inhibitors but also chemotherapy.
In lung cancer patients the rebiopsy is rarely performed, however in the view of intratumor heterogeneity a single biopsy-based analyses for personalized medicine could be a great limitation. Translational implications of tumor heterogeneity.
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Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Clonal architecture of secondary acute myeloid leukemia.