Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced carcinomas has arisen due to several observations in the human population. First, subjects with Laron syndrome who lack GH signaling have significantly lower rates of cancer than people who have normal GH signaling. Second, epidemiologic studies have found strong associations between elevated circulating IGF-1 and the incidence of several common cancers. Third, women who bear children early in life have a dramatically reduced risk of developing breast cancer, which may be due to differences in hormone levels including GH. These observations have motivated multiple studies that have experimentally altered activity of the GH/IGF-1 axis in the context of experimental carcinoma models in mice and rats. Most of these studies have utilized carcinoma models for four organ systems that are also frequent sites of carcinomas in humans: the mammary gland, prostate gland, liver, and colon. This review focuses on these studies and describes some of the most common genetic models used to alter the activity of the GH/IGF-1 axis in experimentally induced carcinomas. A recurring theme that emerges from these studies is that manipulations that reduce the activity of GH or mediators of GH action also inhibit carcinogenesis in multiple model systems.
Paul C Marker, Christopher J Unterberger, and Steven M Swanson
Mina Sattari, Annika Kohvakka, Elaheh Moradi, Hanna Rauhala, Henna Urhonen, William B Isaacs, Matti Nykter, Teemu J Murtola, Teuvo L. J. Tammela, Leena Latonen, G. Steven Bova, Juha Kesseli, and Tapio Visakorpi
Prostate cancer (PCa) is the second-most common cause of male cancer-related death in western industrialized countries, and the emergence of metastases is a key challenge in the treatment of PCa. Accumulating studies have shown that long noncoding RNAs (lncRNAs) play an important role in the regulation of diverse cellular and molecular processes during the development and progression of cancer. Here, we utilized a unique cohort of castration-resistant prostate cancer metastases (mCRPC) and corresponding localized tumors and RNA sequencing (RNA-seq). First, we showed that patient-to-patient variability accounted for most of the variance in lncRNA expression between the samples, suggesting that genomic alterations in the samples are the main drivers of lncRNA expression in PCa metastasis. Subsequently, we identified 27 lncRNAs with differential expression (DE-lncRNAs) between metastases and corresponding primary tumors, suggesting that they are mCRPC-specific lncRNAs. Analyses of potential regulation by transcription factors (TFs) revealed that approximately half of the DE-lncRNAs have at least one binding site for the androgen receptor (AR) in their regulatory regions. In addition, transcription factor enrichment analysis revealed the enrichment of binding sites for PCa-associated TFs, such as FOXA1 and HOXB13, in the regulatory regions of the DE-lncRNAs. In a cohort of prostatectomy-treated prostate tumors, four of the DE-lncRNAs showed association with progression-free time, and two of them (lnc-SCFD2-2, and lnc-R3HCC1L-8) were independent prognostic markers. Our study highlights several mCRPC-specific lncRNAs that might be important in the progression of the disease to the metastatic stage and may also serve as potential biomarkers for aggressive PCa.
Karel Pacak and Roderick Clifton-Bligh
Pheochromocytomas and paragangliomas (PPGLs) are defined as neuroendocrine tumors that produce catecholamines. Many recent advances in their management, localization, treatment, as well as surveillance have significantly improved outcomes for patients with PPGLs or carriers of pathogenic genetic variants linked to the development of these tumors. At present, those advances mainly include the molecular stratification of PPGLs into seven clusters, the 2017 WHO revised definition of these tumors, the presence of specific clinical features pointing toward PPGL, the use of plasma metanephrines and 3-methoxytyramine with specific reference limits to assess the likelihood of having a PPGL (e.g. patients at high and low risk) including age-specific reference limits, nuclear medicine guidelines outlining cluster- and metastatic disease-specific functional (here mainly positron emission tomography and metaiodobenzylguanidine scintigraphy) imaging in the precise diagnostic localization of PPGLs, the guidelines for using radio- vs chemotherapy for patients with metastatic disease, and the international consensus on initial screening and follow-up of asymptomatic germline SDHx pathogenic variant carriers. Furthermore, new collaborative efforts particularly based on multi-institutional and worldwide initiatives are now considered key forces in improving our understanding and knowledge about these tumors and future successful treatments or even preventative interventions.
Wiebke Werner, Katharina Detjen, Alix Bruneau, Isabella Lurje, Natalie Nestel, Henning Jann, Frank Tacke, Bertram Wiedenmann, Christoph Roderburg, and Linda Hammerich
Clinical management of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) remains challenging. We recently introduced FMS-like tyrosine kinase 3 ligand (FLT3LG) as a possible biomarker for a proinflammatory tumor microenvironment. Here, we put a spotlight on the quantitative assessment of classical dendritic cells (cDC) and T cells in the context of FLT3LG mRNA levels in a retrospective study on NET G2/ G3 and NEC of pancreatic and gastric origin. Abundance of cDC and T cells and their relevant subpopulations were determined by immunofluorescent staining and correlated with FLT3LG mRNA levels as well as clinical outcome. Immune cell counts attested highly variable infiltration densities. Samples with presence of cDC or high numbers of T cells exhibited increased FLT3LG expression. Abundance of cDC, defined as HLA-DR+CD11c+ cells with CLEC9a (cDC1) or CD1c (cDC2), as well as CD3+ T cell and CTL (CD8+ CD3+) numbers correlated with FLT3LG mRNA levels and predicted disease-specific survival. Combining FLT3LG and T cell counts further improved this prediction. Therefore, tumor-infiltrating cDC and T cells are prognostic markers in NET G2/ G3 or NEC and FLT3LG mRNA may serve as a simple to use biomarker for a quantitative estimate of their abundance, mandating prospective evaluation in the context of immune-targeted therapies.
Piotr Tomasz Wysocki, Karol Czubak, Anna A. Marusiak, Monika Kolanowska, and Dominika Nowis
Differentiated thyroid cancers (DTCs) are malignancies that demonstrate strong but largely uncharacterized heritability. Germline variants that influence the risk of DTCs localize in disrupted in renal carcinoma 3 (DIRC3), a poorly described long non-coding RNA gene. Here, we investigated the function of DIRC3 in DTCs. Using patient-matched thyroid tissue pairs and The Cancer Genome Atlas data we established that DIRC3 is downregulated in DTCs, whereas high expression of DIRC3 in tumors may reduce the risk of cancer recurrence. DIRC3 transcripts were enriched in cell nuclei, where they upregulated insulin-like growth factor binding protein 5 (IGFBP5), a gene that modulates the cellular response to insulin-like growth factor 1 (IGF1). Silencing DIRC3 in thyroid cancer cell lines (MDA-T32 and MDA-T120) had a dichotomous phenotypic influence: augmented cell migration and invasiveness, reduced apoptosis, but abrogated the MTT reduction rate. Transcriptomic profiling and gene rescue experiments indicated the functional redundancy in the activities of DIRC3 and IGFBP5. Moreover, the reduced level of DIRC3 enhanced the susceptibility of thyroid cancer cells to IGF1 stimulation and promoted Akt signaling via downregulation of the IGFBP5 protein. In conclusion, DIRC3 expression alters the phenotype of thyroid cancer cells and regulates the activity of the IGFBP5/IGF1/Akt axis. Our findings suggest that an interplay between DIRC3 and IGF signaling may play a role in promoting thyroid carcinogenesis.
Francesca Ruggieri, Katharina Jonas, Manuela Ferracin, Michael Dengler, Vanessa Jager, and Martin Pichler
Cancer cells reprogram their metabolism to support their growth. Since the discovery of the Warburg effect, several other metabolic alterations and metabolites have been described in cancer cells, including lactate, glutamine and lipid metabolism reprogramming. Together these alterations provide rapidly dividing tumor cells with metabolic intermediates needed for nucleotide, protein and fatty acid biosynthesis. MicroRNAs are a class of small non-coding RNAs involved in the regulation of virtually all biological pathways. Altered microRNA expression patterns are associated with the onset and development of several diseases, including cancer. Tumor suppressor microRNAs targeting molecules involved in tumor metabolism are frequently downregulated in cancers. Therefore, microRNAs can serve as potential tumor biomarkers and also represent interesting therapeutic targets. This review summarizes recent findings about microRNAs involved in the regulation of tumor metabolism.
Perrine Raymond, Gérald Raverot, and Mirela-Diana Ilie
The purpose of this work was toinvestigate the clinicopathological characteristics at the initial diagnosis of the pituitary tumor and at pituitary carcinoma (PC) diagnosis, alongside with the management and outcomes of PCs, and identify potential prognostic factors and therapeutic strategies associated with the clinical outcome.
PubMed was searched in May 2021 for articles in English and French reporting PCs, the diagnosis of which was made on the presence of metastases. The cases without histological proof and with either another cancer present or an atypical history for a pituitary tumor were excluded.
One hundred and eighty-one articles reporting 207 cases were included, which included 38% corticotroph and 29% lactotroph carcinomas. An initial Ki67 index ≥10% was associated with shorter survival after the initial diagnosis (P = 0.01). Cases with early metastases were associated with both higher initial Ki67 index (P = 0.01) and shorter survival after PC diagnosis (P = 0.001). Interestingly, cases with short survival after PC diagnosis were associated with shorter time between the initial diagnosis and PC diagnosis (P = 0.0006) and had both higher initial Ki67 index (P = 0.003) and higher Ki67 index of the metastasis (P = 0.03). In addition, cases with long survival after PC diagnosis had received more frequently both systemic treatment after PC diagnosis (P = 0.0005) and local treatment for metastases (P < 0.0001).
An initial Ki67 index ≥10% is associated with worse outcome and appears as a promising early marker of future metastasis. Its presence should lead to an intensified surveillance and to a more timely management. Clinicians should not hesitate to use local treatment, independent of whether systemic treatment is used.
Teeranut Asavasupreechar, Ryoko Saito-Koyama, Yasuhiro Miki, Keiichi Tamai, Jiro Abe, Chihiro Inoue, Ikuro Sato, Viroj Boonyaratanakornkit, and Hironobu Sasano
The presence of progesterone receptor (PR) and PR isoform B (PRB) in breast cancer is generally correlated with better clinical outcomes. Additionally, the significance of hormone-independent effects of PR/PRB correlated with better prognosis have been reported in non-small lung cancer (NSCLC). However, the detailed mechanism of that still remains unclear. In this study, we examined how microRNAs (miRNAs) could contribute to tumor inhibition via PR/PRB expression, in order to find miRNAs that have tumor-agnostic effects between breast cancer and NSCLC. We obtained miRNAs data using human tissues of breast cancer and NSCLC from The Cancer Genome Atlas database and PCR array from NSCLC patients of our cohort. Subsequently, we examined the function of the miRNA through in vitro study using breast cancer cell lines. As a result, only let-7b expression was significantly correlated with PR expression in both cancers. Additionally, the expression of let-7b significantly inhibited cell proliferation by inducing PR and PRB expression in breast cancer cell lines. However, the positive correlation of let-7b and PRB required a mediated factor, E2F1, obtained from TGCA databases analysis. In vitro experiments showed that let-7b significantly inhibited E2F1, and E2F1 significantly inhibited PRB. This study revealed that PRB inhibits the proliferation of breast cancer cells by the let-7b-E2F1 interaction. In addition, the immunohistochemical analysis in NSCLC was also consistent with these in vitro data. Our results could contribute to developing novel therapeutic strategies for patients with PR/PRB-positive cancer by targeting let7b or PRB expression in breast cancer and possibly NSCLC.
Arthur S Tischler and Judith Favier
Experimental models for pheochromocytoma and paraganglioma are needed for basic pathobiology research and for preclinical testing of drugs to improve treatment of patients with these tumors, especially patients with metastatic disease. The paucity of models reflects the rarity of the tumors, their slow growth, and their genetic complexity. While there are no human cell line or xenograft models that faithfully recapitulate the genotype or phenotype of these tumors, the past decade has shown progress in development and utilization of animal models, including a mouse and a rat model for SDH-deficient pheochromocytoma associated with germline Sdhb mutations. There are also innovative approaches to preclinical testing of potential treatments in primary cultures of human tumors. Challenges with these primary cultures include how to account for heterogeneous cell populations that will vary depending on the initial tumor dissociation and how to distinguish drug effects on neoplastic vs normal cells. The feasible duration for maintaining cultures must also be balanced against time required to reliably assess drug efficacy. Considerations potentially important for all in vitro studies include species differences, phenotype drift, changes that occur in the transition from tissue to cell culture, and the O2 concentration in which cultures are maintained.
Kristina V. Wells, Margaret L. Krackeler, Maitreyee K Jathal, Mamta Parikh, Paramita M Ghosh, J. Kent Leach, and Damian C Genetos
Prostate cancer (PCa) is an increasingly prevalent health problem in the developed world. Effective treatment options exist for localized PCa, but metastatic PCa has fewer treatment options and shorter patient survival. PCa and bone health are strongly entwined, as PCa commonly metastasizes to the skeleton. Since androgen receptor signaling drives PCa growth, androgen-deprivation therapy whose sequelae reduce bone strength constitutes the foundation of advanced PCa treatment. The homeostatic process of bone remodeling – produced by concerted actions of bone building osteoblasts, bone resorbing osteoclasts and regulatory osteocytes — may also be subverted by PCa to promote metastatic growth. Mechanisms driving skeletal development and homeostasis, such as regional hypoxia or matrix-embedded growth factors, may be subjugated by bone metastatic PCa. In this way, the biology that sustains bone is integrated into adaptive mechanisms for the growth and survival of PCa in bone. Skeletally metastatic PCa is difficult to investigate due to the intwined nature of bone biology and cancer biology. Herein, we survey PCa from origin, presentation, and clinical treatment to bone composition and structure and molecular mediators of PCa metastasis to bone. Our intent is to quickly yet effectively reduce barriers to team science across multiple disciplines that focuses on PCa and metastatic bone disease. We also introduce concepts of tissue engineering as a novel perspective to model, capture, and study complex cancer-microenvironment interactions.