Genomic changes that drive cancer initiation and progression contribute to the co-evolution of the adjacent stroma. The nature of the stromal reprogramming involves differential DNA methylation patterns and levels that change in response to the tumor and systemic therapeutic intervention. Epigenetic reprogramming in carcinoma-associated fibroblasts are robust biomarkers for cancer progression and have a transcriptional impact that support cancer epithelial progression in a paracrine manner. For prostate cancer, promoter hypermethylation and silencing of the RasGAP, RASAL3 that resulted in the activation of Ras signaling in carcinoma-associated fibroblasts. Stromal Ras activity initiated a process of macropinocytosis that provided prostate cancer epithelia with abundant glutamine for metabolic conversion to fuel its proliferation and a signal to transdifferentiate into a neuroendocrine phenotype. This epigenetic oncogenic metabolic/signaling axis seemed to be further potentiated by androgen receptor signaling antagonists and contributed to therapeutic resistance. Intervention of stromal signaling may complement conventional therapies targeting the cancer cell.
Rajeev Mishra, Subhash Haldar, Surabhi Suchanti, and Neil A Bhowmick
Fahmida Rasha, Latha Ramalingam, Lauren Gollahon, Rakshanda Layeequr Rahman, Shaikh Mizanoor Rahman, Kalhara Menikdiwela, and Naima Moustaid-Moussa
Obesity is a complex disease and a global epidemic. It is a risk factor for other chronic diseases including breast cancer, especially in women after menopause. Diverse etiologies underlie the relationship between obesity and breast cancer. Adipose tissue is in part responsible for these interactions. In obesity, adipose tissue undergoes several metabolic dysregulations resulting in the secretion of many pro-inflammatory cytokines, growth factors, and hormones which in turn, can promote tumor microenvironment (TME) formation and cancer progression within the breast tissue. Angiotensin II (Ang II) is a well-known hypertensive hormone produced systemically and locally by the renin-angiotensin system (RAS). Activation of this system in obesity is a potential contributor to local and systemic inflammation in breast adipose tissue. Ang II actions are primarily mediated through binding to its two receptors, type 1 (AT1R) and type 2 (AT2R). RAS inhibitors include angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) which are currently prescribed as safe antihypertensive therapies. Recent studies have explored the potential use of ACE-I and ARBs in breast cancer patients as anti-tumor agents. Therefore, it is vital to understand the role of RAS in breast cancer and identify mechanisms of Ang II and RAS inhibitors in the TME and in obesity and breast cancer crosstalk. In this review, we performed a detailed analysis and discussed mechanisms of Ang II-AT1R interactions in breast cancer with emphasis on obesity-associated breast cancer. We further summarized recent in vitro, in vivo and human studies that used ACE-I/ARB interventions to improve breast cancer outcomes.
Jian Chen, Qingyuan Hu, Hongwei Hou, Shuo Wang, Yunfei Zhang, Yanbo Luo, Huan Chen, Huimin Deng, Hongfu Zhu, Lirong Zhang, Hansong Liu, An Wang, and Yong Liu
Thyroid cancer is the most frequent endocrine tumor with a growing incidence worldwide. However, common diagnostic strategy for thyroid cancer classification is hardly to make a proper diagnosis in some cases. To assist classical approach, this study used metabolomics to screen and validate biomarkers from serum and urinary for papillary thyroid cancer (PTC). Overall, 124 untreated PTC, 76 untreated benign thyroid nodule (BTN), and 116 healthy control (HC) were collected in this study. Thirty-six differential metabolites were screened from non-targeted metabolomics with a discovery sample set in comparison with HC and BTN. Serum β-hydroxybutyrate (BHB), docosahexaenoic acid (DHA), 1-methyladenosine (1-MedA), pregnanediol-3-glucuronide (PdG), urinary nicotinic acid mononucleotide (NAM) and xanthosine (Xan) were validated to be significantly differential by targeted metabolomics in validation set. The logistic regression model incorporating six biomarkers had excellent discrimination from receiver-operating characteristics (ROC) analysis, with area under the receiver-operating characteristic curve (AUC) of 0.943 (95% CI 0.902 to 0.983) and 0.952 (95% CI 0.921 to 0.983) for female alone and female + male samples, respectively. The prediction accuracy and false-negative rate in the real setting of one PTC to ten suspicious nodules were 84.7 and 17.7% with the threshold at probablity of 0.5. Results of a double-blind study for PTC and BTN had true positive value of 100% and true negative value of 91.7%. To conclude, BHB, DHA, 1-MedA, PdG, NAM and Xan are suitable biomarkers for PTC, and logistic regression models with the six biomarkers can be potentially used as clinical diagnosis.
Pedro Marques, Sayka Barry, Eivind Carlsen, David Collier, Amy Ronaldson, Sherine Awad, Neil Dorward, Joan Grieve, Nigel Mendoza, Samiul Muquit, Ashley B Grossman, Frances Balkwill, and Márta Korbonits
Tumour-associated fibroblasts (TAFs) are key elements of the tumour microenvironment, but their role in pituitary neuroendocrine tumours (PitNETs) has been little explored. We hypothesised that TAF-derived cytokines may play a role in tumour aggressiveness and that their release can be inhibited by somatostatin analogues. TAFs were isolated and cultured from 16 PitNETs (11 clinically non-functioning tumours and 5 somatotropinomas). The fibroblast secretome was assessed with a 42-plex cytokine array before and after multiligand somatostatin receptor agonist pasireotide treatment. Angiogenesis and epithelial-to-mesenchymal transition pathway assessment included CD31, E-cadherin and ZEB1 expression. GH3 cells treated with TAF- or skin fibroblast-conditioned medium were assessed for migration, invasion and cell morphology changes. PitNET TAFs secreted significant amounts of cytokines including CCL2, CCL11, VEGF-A, CCL22, IL-6, FGF-2 and IL-8. TAFs from PitNETs with cavernous sinus invasion secreted higher IL-6 levels compared to fibroblasts from non-invasive tumours (P = 0.027). Higher CCL2 release from TAFs correlated with more capillaries (r = 0.672, P = 0.004), and TAFs from PitNETs with a higher Ki-67 tended to secrete more CCL2 (P = 0.058). SST1 is the predominant somatostatin receptor in TAFs, and pasireotide decreased TAF-derived IL-6 by 80% (P < 0.001) and CCL2 by 35% (P = 0.038). GH3 cells treated with TAF-conditioned medium showed increased migration and invasion compared to cells treated with skin fibroblast-conditioned medium, with morphological and E-cadherin and ZEB1 expression changes suggesting epithelial-to-mesenchymal transition. TAF-derived cytokines may increase PitNET aggressiveness, alter angiogenesis and induce epithelial-to-mesenchymal transition changes. Pasireotide’s inhibitory effect on TAF-derived cytokines suggest that this effect may play a role in its anti-tumour effects.
Vasily N Aushev, Kalpana Gopalakrishnan, Susan L Teitelbaum, Humberto Parada Jr, Regina M Santella, Marilie D Gammon, and Jia Chen
Environmental phenols and phthalates are common ingredients in personal care products and some have been implicated in breast cancer progression. We have previously identified genes differentially expressed in response to low-dose exposure to diethyl phthalate (DEP) and methyl paraben (MPB) in a rat model. Herein we explore if these genes are associated with breast cancer mortality in humans. We profiled MPB- and DEP-responsive genes in tumors by NanoString® from a population-based cohort of 606 women with first primary breast cancer among whom 119 breast cancer-specific deaths occurred within 15+ years of follow-up. For each gene, Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results were validated in two publicly available datasets. The following results were obtained. From 107 DEP- and 77 MPB-responsive genes profiled, 44 and 30 genes, respectively, were significantly associated with breast cancer-specific mortality. Some top DEP-responsive genes are novel for breast cancer mortality, such as ABHD14B (for high-vs-low expression, HR 0.36, 95% CI: 0.2–0.5) and TMC4 (HR 0.37, 95% CI: 0.3–0.5); top hits for MPB (SLC40A1 (HR 0.37, 95% CI: 0.3–0.5) and NTN4 (HR 0.39, 95% CI: 0.3–0.6)) are well-known predictors of breast cancer survival. PLEKHA6 was another novel survival predictor, sensitive to hormonal receptor status (HR 0.5, 95% CI 0.3–0.9 for hormonal receptor-positive and HR 3.2, 95% CI 1.7–6.2 for -negative group). In conclusion, tumor expression of DEP- and MPB-responsive genes is associated with breast cancer mortality, supporting that exposure to these chemicals may influence the progression of breast cancer.
Afaf Aldahish, Ajay Kale, Ahmed Aljameeli, and Girish V Shah
Stem cell-like-cancer cells are key drivers of tumor growth, metastasis, and relapse of cancer following remission. Prostate stem cell-like cancer cells isolated from human prostate cancer (PC) biopsies express CD44+/α2β1 hi/CD133+ cell surface markers and can self-renew in vitro. Expression of calcitonin (CT) and its receptor (CTR) is frequently elevated in PCs and activation of CT-CTR axis in non-invasive PC cells induces an invasive phenotype. We investigated whether CT-CTR autocrine axis induces stem cell-like phenotype in two PC cell lines. CT-CTR axis in these cell lines was activated by enforced expression of CTR. The cells were then examined for the changes in the expression of CD44 and CD133, collagen adherence, tumorigenic, metastatic and repopulating characteristics. The activation of CT-CTR axis led to a large increase in adherence to collagen and a remarkable increase of CD44 and CD133 in PC-3 and LNCaP cells. This was accompanied by a strong increase in tumorigenic, metastatic and repopulation properties of PC cells. However, the mutation of CTR-C PDZ-binding site in CTR almost abolished CTR-mediated increases in stem cell-like characteristics of PC cells. These results support an important role for CT-CTR axis in the progression of PC from localized cancer to an aggressive form, and a majority of proinvasive CTR actions may be mediated through its interaction with its partner protein at the PDZ-binding site. These results suggest that CT/CTR can serve as a valuable target to prevent the generation of stem-like PC cells.
Federica Panebianco, Alyaksandr V Nikitski, Marina N Nikiforova, Cihan Kaya, Linwah Yip, Vincenzo Condello, Abigail I Wald, Yuri E Nikiforov, and Simion I Chiosea
ALK fusions are found in various tumors, including thyroid cancer, and serve as a diagnostic marker and therapeutic target. Spectrum and outcomes of ALK fusions found in thyroid nodules and cancer are not fully characterized. We report a series of 44 ALK-translocated thyroid neoplasms, including 31 identified preoperatively in thyroid fine-needle aspirates (FNA). The average patients’ age was 43 years (range, 8–76 years); only one with radiation history. All 19 resected thyroid nodules with ALK fusion identified preoperatively were malignant. Among nodules with known surgical pathology (n = 32), 84% were papillary thyroid carcinomas (PTCs) and 16% poorly differentiated thyroid carcinomas (PDTCs). PTCs showed infiltrative growth with follicular architecture seen exclusively (30%) or in combination with papillary and/or solid growth (37%). Tumor multifocality was seen in 10 (31%) PTC cases. Most PDTC had a well-differentiated PTC component. Lymph node metastases were identified in 10/18 (56%) patients with neck dissection. The most common ALK fusion partners were STRN (n = 22) and EML4 (n = 17). In five cases, novel ALK fusion partners were discovered. All five PDTCs carried STRN-ALK fusion. On follow-up, ten patients were free of disease at 2–108 months, whereas two patients with PDTC died of disease. In summary, ALK fusion-positive thyroid carcinomas are typically infiltrative PTC with common follicular growth, which may show tumor dedifferentiation associated with increased mortality. Compared to EML4-ALK, STRN-ALK may be more common in PDTC, and ~10% of ALK fusions occur to rare gene partners. When ALK fusion is detected preoperatively in FNA samples, malignancy should be expected.
David Taïeb, Abhishek Jha, Giorgio Treglia, and Karel Pacak
In recent years, advancement in genetics has profoundly helped to gain a more comprehensive molecular, pathogenic, and prognostic picture of pheochromocytomas and paragangliomas (PPGLs). Newly discovered molecular targets, particularly those that target cell membranes or signaling pathways have helped move nuclear medicine in the forefront of PPGL precision medicine. This is mainly based on the introduction and increasing experience of various PET radiopharmaceuticals across PPGL genotypes quickly followed by implementation of novel radiotherapies and revised imaging algorithms. Particularly, 68Ga-labeled-SSAs have shown excellent results in the diagnosis and staging of PPGLs and in selecting patients for PRRT as a potential alternative to 123/131I-MIBG theranostics. PRRT using 90Y/177Lu-DOTA-SSAs has shown promise for treatment of PPGLs with improvement of clinical symptoms and/or disease control. However, more well-designed prospective studies are required to confirm these findings, in order to fully exploit PRRT’s antitumoral properties to obtain the final FDA approval. Such an approval has recently been obtained for high‐specific-activity 131I-MIBG for inoperable/metastatic PPGL. The increasing experience and encouraging preliminary results of these radiotherapeutic approaches in PPGLs now raises an important question of how to further integrate them into PPGL management (e.g. monotherapy or in combination with other systemic therapies), carefully taking into account the PPGLs locations, genotypes, and growth rate. Thus, targeted radionuclide therapy (TRT) should preferably be performed at specialized centers with an experienced interdisciplinary team. Future perspectives include the introduction of dosimetry and biomarkers for therapeutic responses for more individualized treatment plans, α-emitting isotopes, and the combination of TRT with other systemic therapies.
Moray J Campbell
The 3D organization of the genome within the cell nucleus has come into sharp focus over the last decade. This has largely arisen because of the application of genomic approaches that have revealed numerous levels of genomic and chromatin interactions, including topologically associated domains (TADs). The current review examines how these domains were identified, are organized, how their boundaries arise and are regulated, and how genes within TADs are coordinately regulated. There are many examples of the disruption to TAD structure in cancer and the altered regulation, structure and function of TADs are discussed in the context of hormone responsive cancers, including breast, prostate and ovarian cancer. Finally, some aspects of the statistical insight and computational skills required to interrogate TAD organization are considered and future directions discussed.
Livia Lamartina, Sophie Leboulleux, Marie Terroir, Dana Hartl, and Martin Schlumberger
Low-risk papillary cancers, which represent the vast majority of thyroid cancers diagnosed today, do not require aggressive treatment or follow-up. Initial treatment consists of a total thyroidectomy without prophylactic lymph node dissection. A hemithyroidectomy is an alternative in some patients with an intrathyroidal tumor and with a normal contralateral lobe at pre-operative neck ultrasonography. The use of post-operative radioiodine should be restricted to selected patients. Follow-up at 6–18 months is based on serum thyroglobulin (Tg), Tg-antibody determination and neck ultrasonography. In the absence of any abnormality (excellent response to treatment), the risk of recurrence is extremely low and follow-up may consist of serum TSH monitoring that is maintained in the normal range, and a Tg and Tg-antibody titer determination every year. There is no need for referral to a specialized center. In patients with detectable serum Tg or detectable Tg antibodies, the trend over time of these markers on levothyroxine treatment will dictate subsequent follow-up: a decreasing trend is reassuring, but an increasing trend should lead to imaging, starting with neck ultrasonography.