Neuroendocrine transformation in tumors – trans-differentiation or tumor heterogeneity?
Carmen Ardeleanu1,2, Florin Băcanu3, Dana Terze1
1. Onco Team Diagnostic, Royal Hospital Bucharest, Romania, 2. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 3. Sanador Hospital, Bucharest, Romania
The neuroendocrine character of tumors from different organs imprints certain particularities that influence both their mode of production and their name. Thus, tumors from organs with cells with neuroendocrine secretion (medullary adrenal, parathyroid, thyroid or even the digestive tract and lung) have specific origin cells and are classified according to certain parameters, in good, moderate or poorly differentiated neuroendocrine tumors. For organs where no neuroendocrine cells (mammary gland, prostate, kidney, cervix) are present, the origin cell is difficult to determine in the case of a tumor with a neuroendocrine immunophenotype. Therefore, their classifications include neuroendocrine tumors and tumors with neuroendocrine character/differentiation (Rosen, 2017). However, there is the possibility of a neuroendocrine tumor in the recurrence of an epithelial tumor, for example in the prostate, mammary gland or lung. It can be considered that their occurrence is achieved through a trans-differentiation process, under the influence of transcriptional factors of some stem cell genes, such as SOX2 (Karachaliou, 2013). Nevertheless, it is not possible to exclude the possibility that in any epithelial tumor there are initially (according to the tumor heterogeneity) a number of cells of neuroendocrine character that during the clonal expansion of the tumor to activate (Kato, 2019). The trans-differentiation process has been studied experimentally, identifying a number of transcriptional factors that intervene in signaling pathways related to differentiation and proliferation such as Wtn/beta-Catenin (Sinner, 2004), EGFR-Src-AKT (Singh, 2012), IL8-CXCRC2-p53 (Huang, 2005), PI3K-AKT-mTOR (Lee, 2016), IL6-STAT3 (Yao, 2018), MAPK-ERK etc. A known pattern of neuroendocrine transformation is that of prostate carcinoma, secondary to anti-androgenic therapies. All these factors that produce the transformation could become therapeutic targets.
Physician burnout: healing the healer
Department of Psychiatry and Human Behavior, University of California, Irvine, USA
This is not a fair fight. Medical school and residency brainwashes you over 10 years. At that time we develop a set of habits that in medical school and residency are very useful. However, postponing self-care, doing it all ourselves to make sure is “done right” and working with sick patients in bad affective states start wearing on us. Sir William Osler said: “The practice of medicine will be very much as you make it – to one a worry, a care, a perpetual annoyance; to another, a daily job and a life of as much happiness and usefulness as can well fall to the lot of man”. However, wishing burnout away is not working in this day and age. The concept of burnout emerged 50 years ago to describe the clinic staff caring for vulnerable patients in free clinics. Since then, the term burnout has been used to describe job-related stress in health practice environment. Based on the foundational work of Maslach in 1980’s, researchers have described burnout as a combination of emotional exhaustion, depersonalization, and low sense of accomplishment. This is caused by the chronic stress of medical practice. Pragmatically, burnout is associated with more medical errors, decreased professional work effort, and lower patient satisfaction. In this presentation, I will describe the psychological mechanisms involved, and how to recognize and address burnout in ourselves and in our colleagues.
Genetic and molecular alterations for the treatment of metastatic colorectal cancer
Gabriela E. Chiorean
University of Washington, Seattle and Fred Hutchinson Cancer Research Center, USA
Colorectal cancer is the second leading cause of cancer mortality in Romania and worldwide (880,000 cases yearly). Approximately 25% of newly diagnosed patients have metastatic disease from the outset, and among those with initially early-stage operable disease, 50% progress to develop metastases. Chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan represents the standard of care for the treatment of metastatic colorectal cancer and it confers an average life expectancy of three years when used sequentially. Targeted therapies using anti-vascular endothelial growth factor/receptor (VEGF/VEGFR) and anti-epidermal growth factor receptor (EGFR) antibodies have been often used in combination with multi-agent chemotherapy and add an average of three months to overall survival. Anti-cancer treatments for many solid tumors have recently evolved from non-selective chemotherapy to targeted therapies, depending on driver genomic mutations identified in tumor or liquid biopsies. Few novel biomarkers have been discovered for colorectal cancers, but wild type RAS (KRAS/NRAS; 40-50%), BRAF V600E mutations (5-9%), HER2/ERBB2 amplifications (3%), microsatellite instability (MSI-high) (3-5%), and NTRK1,2,3 fusions (<1%) are molecular alterations which can guide the treatment with effective targeted therapies: anti-EGFR antibodies for RAS wild type tumors, the combination EGFR with BRAF and MEK blockade for BRAF V600E mutations, anti-HER2 antibodies for HER2 amplifications, anti-PD1 +/- anti-CTLA4 immune checkpoint inhibitors for MSI-high tumors, and NTRK tyrosine kinase inhibitors for NTRK fusions. Discovering novel targeted therapies and combinations, means of preventing treatment resistance, and rational pathways of rendering microsatellite stable (MSS) colorectal cancer responsive to immune checkpoint inhibition and immunotherapies in general are areas of intense research.
The advantages of thoracoscopic esophagectomy with lymphadenectomy through triple minimally invasive approach (thoracoscopy and laparoscopy)
Silviu Constantinoiu1, Mircea Gheorghe1, Florin Achim1, Adrian Constantin1, Petre Hoară1, Laura Popa2, Rodica Bîrlă1
1. Center of Excellence in Esophageal Surgery, “St. Mary” Clinical Hospital, Bucharest; “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania. 2. Intensive Care Department, “St. Mary” Clinical Hospital, Bucharest, Romania
Introduction. Esophagectomy is a major surgical procedure with morbidity and mortality related to the patient’s condition, stage of the disease, complementary treatments and surgical experience. Minimally invasive esophagectomy can lead to decreased perioperative morbidity and mortality, with good early outcomes regarding the patients’ quality of life. Materials and method. We present the experience of the Center of Excellence in Esophageal Surgery in total minimally invasive esophagectomy through the modified McKeown triple approach, thoracoscopic laparoscopic and cervical, as initial experience, from a series of minimally invasive procedures for esophageal cancer. Results. In the last three years, 17 minimally invasive esophagectomies have been performed, through different procedures, thoracoscopic, laparoscopically assisted and total thoraco-laparoscopic. We present the minimally invasive thoraco-laparoscopic esophagectomy procedure, followed by esophageal reconstruction with stomach (gastric pull-up technique) and cervical esophago-gastric anastomosis and feeding jejunostomy. The operative times were: thoracic 120 minutes, abdominal 130 minutes, and cervical 50 minutes, with a total of 300 minutes. There was a favorable postoperative evolution, with early feeding on jejunostomy within 24 hours postoperatively, with the control of cervical anastomosis in the 6th day and discharge without symptoms in the 10th day postoperatively. Follow-up at 30 and 90 days, without complications. Conclusions. The solid experience in open esophageal surgery allows us to perform complex minimally invasive surgical procedures with a short learning curve, with low perioperative morbidity and mortality. Due to the minimally invasive approach, the evolution was simple, without the specific complications of an advanced oncologic surgery, with a good quality of life in the postoperative period. Long-term follow-up will be able to confirm the results from the literature regarding survival which is at least equivalent with survival of patients who underwent open esophagectomy.
CX3CR1 identifies PD-1 therapy-responsive CD8 T cells that may mediate the response to combined chemo-immunotherapy for metastatic melanoma
Mayo Clinic, Florida, USA
Although immune checkpoint inhibitors have been reported to result in durable clinical benefit in a subset of patients with advanced cancer, primary or acquired resistance is common and is a pressing challenge in the management of these patients. Notably, cancer patients whose tumors have progressed upon anti-PD-1 therapy have been found to benefit from the addition of salvage chemotherapy, even though cytotoxic chemotherapy is classically viewed as toxic to immune cells. However, the mechanism responsible for the successful clinical outcomes of chemo-immunotherapy is not completely understood. Here we show that a subset of CD8+ T cells expressing the chemokine receptor CX3CR1 are able to withstand cytotoxic chemotherapy and significantly increased in patients with metastatic melanoma who responded to combined chemo-immunotherapy (paclitaxel and carboplatin with PD-1 blockade). The CX3CR1+CD8+ T cells have an effector memory phenotype and the ability to efflux chemotherapy drugs via the ABCB1 transporter. Our preclinical modes have also identified an optimal sequencing of chemo-immunotherapy that resulted in an increase of CX3CR1+CD8+ T cells.
Stromal vulnerabilities in liver cancers
Dan G. Duda
Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, USA
Surgical treatments offer the chance for cure in liver cancers such as hepatocellular carcinoma (HCC). However, many of the resected or transplanted patients experience disease progression. Moreover, many patients present with unresectable disease at diagnosis. In such cases, until recently, the available treatment options – local and systemic – have been limited in efficacy which led to dismal survival rates in advanced HCC. But more recent developments in oncology have offered renewed hope for advanced HCC patients. Hypofractionated radiation has shown feasibility and promise in unresectable HCC setting, and is now being tested in a randomized phase III trial (clinicaltrials.gov identifier NCT03186898). Antiangiogenic agents have strongly impacted the management of advanced HCC, with multiple drug options in first-line setting (sorafenib, lenvatinib) and second-line setting (regorafenib, cabozantinib, ramucirumab). Notably, immunotherapy with anti-PD-1/PD-L1 antibodies has shown real potential to transform advanced HCC therapy, both in first-line and second-line settings. Finally, the combinations of these new strategies are very attractive approaches, as they promise durable and profound responses in advanced HCC. But in order to achieve this promise, these concepts require greater understanding based on mechanistic preclinical studies and validation in correlative studies in clinical trials as a basis to establish optimal combinatorial strategies. I will present results from clinical correlative studies and preclinical models of these diseases performed at our institution and in collaboration with other American and European investigators. The insights gained from this “bench-to-the-bedside and back” approach raise the hope for a more efficient development of targeted agents in advanced HCC, with the goal of increasing survival in patients afflicted with this aggressive and deadly disease.
Hematopoietic versus non-hematopoietic. That is the question
Children’s Hospital Minnesota, USA
The traditional morphology-based classification of hematologic neoplasms is currently complemented by an ever-increasing array of immunophenotypic, cytogenetic and molecular markers. The current WHO classification establishes the guidelines for an integrated diagnosis combining clinical data, morphology, immunophenotyping and genetic features of hematological malignancies. Adequate clinical management relies on both diagnostic accuracy and an expanding number of targeted therapeutic agents geared towards underlying pathological and molecular abnormalities responsible for tumorigenesis. In contrast, the risk of diagnostic errors in hematology persists due to both technical errors and lack of expertise. This presentation reviews a range of potential pitfalls in the diagnosis of hematological malignancies. For example, nonspecific staining of blasts with nonhematopoietic antigens such as vimentin, HMB-45, thyroglobulin, and actin should not be misinterpreted as evidence of metastatic carcinoma. Neuroendocrine tumors are typically positive for CD56, but like all epithelial neoplasms, they are consistently CD45 negative and positive for other epithelial markers. Awareness of such pitfalls – some common, while others are rare – carries vital clinical importance in disease management. Arriving to a final diagnosis of a hematological malignancy relies upon a combination of clinical information, good laboratory techniques, access to appropriate diagnostic tools, good communication with our clinical colleagues and the experience of the hematopathologist.
Review of tyrosine kinase inhibitor therapy in non-small cell lung cancer (NSCLC)
Abil. Dr. Alexandru C. Grigorescu
“Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania
Nowadays there is an important change in the systemic therapy of lung cancer, especially for the non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKI) therapy for patients with mutations in the EGFR (epidermal growth factor receptor) gene has been shown to improve the progression-free survival (PFS), as well as overall survival (OS). I will present the second and the third generation of TKIs which, in some studies, have proven to improve PFS or OS. I will focus particularly on osimertinib, a third-generation TKI EGFR inhibitor, that has also a direct inhibitory effect on the T790M mutated protein, commonly (approximately 60% of the cases) associated with TKI EGFR inhibitors resistance. I will present the main studies that have introduced TKIs to the clinical practice and, also, other therapeutic combinations proven to increase the effectiveness and outcome of the resistance which is consistently associated with TKIs treatment. Another approach in this review is to present the sequencing of TKI therapy, which is still controversial.
Clinical significance of epithelial to mesenchymal transition molecular markers in pancreatic ductal adenocarcinoma
Răzvan Iacob1,2, Andrei Şorop1, Ana-Maria Pantazica1, Ioana Manea1,2, Elena Moise1, Alina Ghionescu1, Maria Sîrbu1, Vlad Herlea1,2, Adina Croitoru1,2, Cristian Gheorghe1,2, Simona Dima1,2, Irinel Popescu1,2
1. Centre of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania. 2. Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
Background. Epithelial to mesenchymal transition (EMT) is one of the key factors contributing to aggressiveness of pancreatic ductal adenocarcinoma by increasing metastatic potential. New therapies combining cytotoxic drug agents with EMT inhibition are currently emerging, thus the identification of PDAC cases with a distinct EMT profile is mandatory. Materials and method. Thirty-five patients with resectable PDAC were included in the analysis. Quantitative gene expression has been conducted for transcription factors controlling EMT process – FOXA2, GATA6, SNAIL, SLUG, TWIST1, TWIST2, ZEB1. Relative gene expression has been quantified for each gene using tumor-non-tumor tissue pairs and beta-actin as housekeeping gene. The correlations of gene expression within the transcription factors network was investigated by analysis of covariance, and correlations patterns were used in order to define key transcriptional profiles specific to the EMT process. Prognostic value for tumor recurrence and survival were assessed by Cox proportional hazards model. Recurrence free survival and overall survival were estimated by Kapan-Meier method. Results. Significant overexpression of EMT transcription factors was identified in: 82.3% of cases for Twist1, 48.5% for SNAIL, 42.6% for SLUG, 35.3% for TWIST2, and 32.3% for ZEB1. Significant downregulation was registered in 64.7% of subjects for GATA6 and in 58.8% for FOXA2. Both SNAIL and SLUG were positively correlated with TWIST2 and ZEB1 (p=0.0027 and p=0.03; p=0.02 and p=0.02, respectively). Based on the correlation matrix, there were five EMT profiles generated: FOXA2down/SNAILup, GATA6down/TWIST1up, GATA6down/ZEB1up, TWIST1up/SNAILup, and TWIST1up/ZEB1up. Multivariate survival analysis has indicated that all these profiles, excepting GATA6down/TWIST1up, are independent predictors for tumor recurrence and patient survival. According to Kaplan-Meier survival analysis, EMT profile characterized by GATA6 downregulation and ZEB1 overexpression has the worst prognosis, with 3 months time to tumor recurrence and 9 months survival time (p=0.01 and p=0.008, respectively). Conclusions. Our study has identified by relative gene expression quantification EMT profiles that independently predict both time to recurrence and survival in resectable PDAC patients. In our study group, cases defined by Gata6 downregulation/Zeb1 upregulation had the worst prognosis.
The Gene Master Regulators of tissues and cells collected from patients with blood, lung, kidney, prostate or thyroid cancer
Personalized Genomics Laboratory, Prairie View A&M University, Texas, USA
Most cancers occur from nowhere, without being inherited or directly caused by a steady deficient diet (affecting the microbiome), exposure to radiation or carcinogenic toxins, or bad habits (like smoking), although such risk factors increase the chances of the “bad luck”. Tumors are heterogeneous, composed of regions with distinct characteristics, some of them malignant, and some others preserving the normal features of the tissue. In spite of a very rich literature, there is not yet a comprehensive explanation of cancer development, nor a perfect therapeutic solution. Moreover, with all similarities, each human is unique and has a unique lifeline, so, although a trained pathologist can recognize the cancer type, the tumors are not identical, nor do they develop identically or respond identically to treatment. Therefore, instead of targeting the same alleged gene biomarker for all humans with a particular cancer form, we devised a method by which the cancer of the actual patient itself indicates us what genes are now commanding it. We call these commanders “gene master regulators” (GMRs) and identify them by profiling the gene expression in tumor biopsies or blood samples (pending on the suspected cancer type) using RNA sequencing or microarray platforms. Here, we prove that cancer nuclei and surrounding normal tissue are governed by distinct GMRs and that smart manipulation of a GMR’s expression selectively affects cancer cells. The method, consistent with our Genomic Fabric Paradigm, relies on an original mathematical algorithm that establishes the gene hierarchy from the transcriptomic profiles of tumor biopsies based on their Gene Commanding Height (GCH). GCH is a composite measure of gene expression control and coordination with major functional pathways. We present the validation of the approach using microarray data obtained in our previous NYMC laboratory by profiling human kidney, thyroid, blood, lung and prostate cancer samples. The GMR approach provides the most legitimate targets for cancer gene therapy. It is also personalized and time-sensitive because the GMR hierarchy is unique for each patient and changes slowly during cancer development.
Whole-body MRI – its role in the detection and post-therapeutic tracking of bone metastases in the high-precision oncology era
Monza Metropolitan Hospital Bucharest, Romania
The goal of this presentation is to propose to oncology clinicians a new paradigm in the imagistic approach of a newly discovered breast cancer patient, as well as in the follow-up of cases already known during therapy and post-therapy. General drivers for whole-body MRI in oncology practice are: 1) poor performance of conventional imaging when detecting disease, assessing tumor volume or therapy response; 2) poor performance of serum markers in assessing response – CA 15-3 in breast cancer, PSA in castrate resistant prostate cancer etc. The current imaging tools lead to poor confidence for assigning clinical states and addressing therapy benefits. They are limited tools because: they are unable to accurately depict the presence or extent of the metastatic disease; they have limited ability to depict heterogeneity of response in patients with bone disease; they are unable to identify the patients which are not benefiting early after starting the treatment. MET-RADS – standard for WB-MRI in metastatic cancer – will develop new criteria to assess metastatic bone disease. WB-MRI has the potential to alter the diagnostic thinking when assessing response by adding categories that positively assess the success of therapies in bone disease (NOT just the absence of progression).WB-MRI could help deliver the promise of precision oncology for patients with malignant bone disease – “right treatment, right patient, right time for the right duration”. The validation and qualifications are currently incomplete.
The association of targeted therapies, immunotherapies and radiotherapy in the treatment of brain metastasis from cutaneous malignant melanoma
Dan Jinga, Ana Băncilă, Lucian Bratu
Neolife Bucharest Medical Center, Romania
Malignant melanoma represents the third cause of brain metastasis produced by solid tumors, after lung cancer and breast cancer. The development of brain metastasis is correlated with significant neurologic deficits and with reduced anticipated overall survival of patients diagnosed with malignant melanoma. The median overall survival for untreated brain metastasis is only 3 months, compared with 9 months for the patients treated with classic systemic treatments (chemotherapy). The new modern local treatments, such as stereotactic radiosurgery, and the new systemic treatments, such as anti-BRAF targeted therapies and immunotherapies introduced in the last years all over the world, including in Romania, improved therapeutic results. Materials and method. From our personal data including patients with solid tumors treated in the last 15 years, we identified 299 cases with cutaneous malignant melanoma (10.5% from the total number of the patients). The median age of diagnosis was 52 years old, and the median Breslow Index was 3.12 mm. The median disease-free survival was 40 months, and the median overall survival was 48 months for the cutaneous malignant melanoma population. Thirty-nine patients (13%) were diagnosed with brain metastasis – 15 patients from the diagnosis of the disease and 18 patients with progressive brain metastasis from stages I, II and III. For six patients, there are no data regarding the initial stage of disease. Results. The brain metastatic cutaneous malignant melanoma had a higher median Breslow Index compared with the general population diagnosed with cutaneous malignant melanoma (4.74 mm compared with 3.12 mm), and a median disease survival significantly reduced (33 months compared with 40 months). The median survival for the IIIC and IV stages was significantly reduced compared with the general population with cutaneous malignant melanoma (22.6 months compared with 48 months). Out of the total number of patients with brain metastatic cutaneous malignant melanoma, 30% were treated by surgery, 60% with palliative whole-brain irradiation and 10% with combined local treatments and best supportive care. Regarding systemic treatments, 25% of the patients received modern therapies like anti-BRAF and immunotherapy drugs. Conclusions. Using new local and systemic treatments improved the survival of patients with brain metastasis from cutaneous malignant melanoma. The study presents the main treatments, their associations, and a complex multidisciplinary approach.
Tumor biopsy: are we ready for the “liquid” revolution?
Anatomic Pathology and Cytopathology, Loyola University Medical Center, University of Chicago Medical Center
Oncology traditionally relied on morphologic examination of neoplastic tissues and individual cells as its main diagnostic instruments, while molecular biology joined the diagnostic armamentarium during the last two decades. Liquid biopsy represents a novel minimally invasive alternative to surgical biopsy for molecular markers in blood and other body fluids of cancer patients. It overcomes the hurdles in the clinical assessment of tumors derived due to lack of accessibility to the tumor tissue and its clonal heterogeneity. Additionally, body fluid molecular analysis reflects the genetic fingerprint of primary and metastatic lesions and provides real-time monitoring of tumor evolution, holding a great promise for personalized medicine. Past technical hurdles have been mitigated by newly developed techniques such as next-generation sequencing, expanding the clinical applications of liquid biopsy. Initially correlated to disease prognosis, liquid biopsy derived data are currently used for cancer diagnosis, most importantly for the prediction of response or resistance to therapy. The identification of specific mutations in target genes can aid in therapeutic decisions, both in the appropriateness of treatment and in the advanced identification of secondary resistance, aiming to early diagnose disease progression. This presentation will review classical cytology diagnostic methods followed by describing liquid biopsy aspects, including tumor-derived exosomes, circulating tumor cells, tumor-educated platelets, and circulating tumor miRNAs and mRNAs.
Optical techniques for intraoperative guidance of cancer surgery
PhD, Professor of Biomedical Engineering and Neurological Surgery, University of California, Davis, USA
Fluorescence measurements provide information about biochemical, functional and structural changes in fluorescent bio-molecular complexes in tissues and cells, including structural proteins, enzyme metabolic co-factors, lipid components, and porphyrins. Typically, these changes are a result of either pathological transformation, or therapeutic intervention. We investigate time-resolved fluorescence spectroscopy (TRFS) and fluorescence lifetime imaging microscopy (FLIM) techniques that utilize label-free fluorescence lifetime contrast to detect such changes in vivo. This presentation will overview clinically-compatible TRFS and FLIM instrumentation and present studies that demonstrate the diagnostic potential of these optical techniques in neurosurgical procedures. We show that intrinsic fluorescence signals provide useful contrast for the intraoperative guidance of brain tumors surgical resection and delineation of radiation-induced injury from tumor recurrence.
Unique epigenetic characteristics of cancer stem cells in ovarian cancer
Northwestern University, Feinberg School of Medicine, Chicago, USA
The development of resistance to chemotherapy was linked to persistence of cancer stem cells (CSCs). These are characterized by the ability to self-renew, grow as spheres, differentiate and generate tumors in immunodeficient mice. They are resistant to traditional forms of treatment, including chemotherapy and radiotherapy. Building on our previous work showing that ovarian CSCs residual after treatment with platinum display increased DNA methylation, we hypothesized that other epigenetic modifications occur, promote a stem-like phenotype, and render CSCs vulnerable to epigenome modifying agents. To begin to address this question, we used partial wave spectroscopy to visualize chromatin at the nanoscale level, the Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) to map accessible promoter regions, and proteomic analysis to measure histone marks in CSCs versus non-CSCs. We found less open chromatin associated with repressive histone marks in CSCs versus non-CSC, defined specific gene networks activated in CSCs versus non-CSCs, and showed that various epigenetic regulators blocked chromatin compaction and transcription heterogeneity in CSCs. We also identified increased expression of the H379 histone methyltransferase Dot1L in CSCs versus non-CSCs and demonstrated that Dot1L inhibitors and Dot1L knock down blocked stemness features, including sphere formation, stemness associated transcription factors, and tumorigenicity in vivo. Our data support that epigenetic modifiers suppress CSCs by de-repressing chromatin and promoting activation of differentiation pathways. The results of this project are immediately applicable to ovarian cancer, but may have broader implications for other platinum-resistant solid tumors.
Tumor exosomes: from mediators of systemic disease to biomarkers of metastatic spread
Weill Cornell Medical College, New York, USA
Cancer is a systemic disease and metastasis to distant vital organs such as lung, liver and brain is the most devastating feature of cancer progression, responsible for over 90% of cancer-associated deaths. Reciprocal interactions between tumor cells and their local and distal microenvironments as well as the immune system drive cancer progression and metastasis, immunosuppression and therapy resistance. Our investigation of the tumor-secreted factors that mediate the crosstalk between tumors and cells in the remote metastatic microenvironment has led to the discovery that tumor-secreted microvesicles, known as exosomes, alter the microenvironment at future sites of metastasis to form pre-metastatic niches, creating a favorable “soil” for incoming metastatic “seeds”. Unbiased proteomic profiling of exosomes revealed distinctive protein expression patterns, and analysis of plasma exosomes from cancer patients that later developed site-specific metastasis revealed that exosome protein content could predict metastatic spread to lung, liver and brain. Importantly, exosomes have complex cargo that in addition to proteins includes DNA, coding and non-coding RNAs, as well as lipids and metabolites, all of which have biomarker potential. Through application of novel technologies, such as asymmetric flow field-flow fractionation to exosome research, we have recently unraveled the heterogeneity of exosome populations, identifying two new distinct exosome subpopulations (large and small exosome vesicles) and demonstrating the existence of a population of novel nanoparticles with distinct structure, composition and function termed “exomeres”. Undoubtedly, further insight into exosome biogenesis, molecular composition, biodistribution, and functions will open new avenues for translational studies of the diagnostic, prognostic and therapeutic applications of extracellular vesicles/particles.