
Michele Carbone, MDUniversity of Hawaiʻi at Mānoa | UH Manoa · Cancer Center
Michele Carbone, MD
Board Certified in Anatomic Pathology, University of Chicago - The Pritzker School of Medicine
About
357
Publications
35,769
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
20,268
Citations
Introduction
Dr. Michele Carbone's research focuses on malignant mesothelioma. One of the puzzles he has tried to solve is why some people exposed to asbestos develop mesothelioma while others do not. This central question has informed most of his work.
Dr. Michele Carbone is a strong proponent of multidisciplinary team research. His research team includes scientists who specialize in different disciplines including pathology, surgery, genetics, molecular biology, geology and mineralogy, and public health.
Additional affiliations
January 2015 - present
University of Hawaiʻi
Position
- Managing Director
Description
- My team studies mechanisms of asbestos carcinogenesis and uncovered the role of SV40, of genetics and of erionite as co-factors in mesothelioma. Recently we identified that mutation of the gene BAP1 causes an epidemic of mesothelioma in certain families.
Education
June 1991 - May 1993
June 1991 - June 1993
June 1985 - June 1988
Publications
Publications (357)
Fructose metabolism has emerged as a significant contributor to cancer cell proliferation, yet the underlying mechanisms and sources of fructose for cancer cells remain incompletely understood. In this study, we demonstrate that cancer cells can convert glucose into fructose through a process called the AKR1B1 -mediated polyol pathway. Inhibiting t...
We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 ( BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we...
Mesothelioma is a cancer typically caused by asbestos. Mechanistically, asbestos carcinogenesis has been linked to the asbestos-induced release of HMGB1 from the nucleus to the cytoplasm, where HMGB1 promotes autophagy and cell survival, and to the extracellular space where HMGB1 promotes chronic inflammation and mesothelioma growth. Targeting HMGB...
Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretio...
Diffuse Malignant mesothelioma is a very aggressive cancer that is related to asbestos exposure. We found previously that following asbestos deposition in the pleura and in the peritoneum, mesothelial cells release HMGB1 that attract granulocytes and macrophages that, in turn, secrete HMGB1. It was unknown whether the primary source of HMGB1 that d...
Overview
Malignant pleural mesothelioma is an aggressive malignancy with an incidence that may be peaking worldwide. While the majority of patients do ultimately die of this disease, there have been substantial treatment and diagnostic shifts over the past decade that may improve long‐term outcomes. These changes include worldwide interest in defin...
BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressiv...
Occupational disease is an important public health problem of the 21st century. Occupational disease still accounts for many preventable illnesses and injuries in the workplace. It is important to incorporate modern knowledge of disease epidemiology and cutting-edge diagnostic methods and treatment with the most recent developments in the managemen...
Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional s...
The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma; less frequently breast cancer, several types of skin carcinomas and other tumor types. Mesotheliomas in these patients are significantly less aggressive and patients require a m...
Objective:
The aim of this review is addressing the mechanisms of asbestos carcinogenesis, including chronic inflammation and autophagy-mediated cell survival, and propose potential innovative therapeutic targets to prevent mesothelioma development or improve drug efficacy by reducing inflammation and autophagy.
Background:
Diffuse malignant ple...
Exposure to asbestos and to other carcinogenic fibers causes mesothelioma, an aggressive tumor with poor prognosis. Tumorigenesis originates from a chronic inflammatory process driven by high mobility group box 1 (HMGB1) and the activation of the inflammatory factors, which induce the secretion of tumor necrosis factor-α (TNF-α) and other cytokines...
Mesothelioma has been for many years the example of a malignancy induced exclusively by exposure to the environmental carcinogen asbestos. In recent years additional fibers, erionite and antigorite for example, and therapeutic ionizing radiation have been shown to cause mesothelioma. Most importantly, molecular genetic studies conducted by our team...
Significance
We found that the probability of carrying heterozygous germline BLM mutations is significantly higher among mesothelioma patients than in the general population. In vitro and in vivo experiments suggest that heterozygous BLM mutations increase susceptibility to mesothelioma. BLM -mutation carriers are at higher risk of developing mesot...
Malignant pleural mesothelioma (MPM) is an asbestos-related neoplasm that can only be treated successfully when correctly diagnosed and treated early. The asbestos-exposed population is a high-risk group that could benefit from sensitive and specific blood- or tissue-based biomarkers. We review recent work with biomarker development in MPM and lite...
High-mobility group box 1 (HMGB1) was initially recognized as a ubiquitous nuclear protein involved in maintaining the nucleosome integrity and facilitating gene transcription. HMGB1 has since been reevaluated to be a prototypical damage-associated molecular pattern (DAMP) protein, and together with its exogenous counterpart, pathogen-associated mo...
Significance
Millions of people have been exposed to asbestos and are at increased risk of developing mesothelioma, an aggressive malignancy resistant to current therapies. Here, we elucidate critical steps in asbestos carcinogenesis: asbestos induces the release of high mobility group box 1 that triggers autophagy. Autophagy activation constitutes...
Background:
Malignant Pleural Mesothelioma (MPM) is an asbestos related neoplasm which can only be treated successfully when correctly diagnosed and treated in early stages. The asbestos exposed population serves as a high risk group which could benefit from sensitive and specific blood based or tissue based biomarkers. This review details the rec...
p>Among more than 200 BAP1 -mutant families affected by the “BAP1 cancer syndrome,” nearly all individuals inheriting a BAP1 mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadica...
Cell division and organismal development are exquisitely orchestrated and regulated processes. The dysregulation of the molecular mechanisms underlying these processes may cause cancer, a consequence of cell-intrinsic and/or cell-extrinsic events. Cellular DNA can be damaged by spontaneous hydrolysis, reactive oxygen species, aberrant cellular meta...
Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States,...
The accurate diagnosis of mesothelioma is critical for the appropriate clinical management of this cancer. Many issues complicate making the diagnosis of mesothelioma including the presence of reactive mesothelial cells in benign pleural effusions, the heterogeneity of mesothelioma histopathology, the relatively high incidence of other epithelial m...
Galectin-9 has emerged as a promising biological target for cancer immunotherapy due to its role as a regulator of macrophage and T-cell differentiation. In addition, its expression in tumor cells modulates tumor cell adhesion, metastasis, and apoptosis. Malignant mesothelioma (MM) is an aggressive neo-plasm of the mesothelial cells lining the pleu...
Purpose:
We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years.
Patients and methods:
Over the course of 7 years, 79 patients with MM met the four...
The tumor suppressor and deubiquitinase (DUB) BAP1 and its Drosophila ortholog Calypso assemble DUB complexes with the transcription regulators Additional sex combs-like (ASXL1, ASXL2, ASXL3) and Asx respectively. ASXLs and Asx use their DEUBiquitinase ADaptor (DEUBAD) domain to stimulate BAP1/Calypso DUB activity. Here we report that monoubiquitin...
The relative contribution of intrinsic genetic factors and extrinsic environmental ones to cancer aetiology and natural history is a lengthy and debated issue. Gene–environment interactions (G x E) arise when the combined presence of both a germline genetic variant and a known environmental factor modulates the risk of disease more than either one...
On March 28th - 29th 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee (TMSC), the International Association for the Study of Lung Cancer (IASLC) and the Mesothelioma Applied Research Foundation (MARF), convened the NCI-IASLC-MARF Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meet...
We discovered that heterozygous germline BAP1 mutations (BAP1+/-) cause a novel cancer syndrome that we named “The BAP1 cancer syndrome” characterized by development of malignant mesothelioma (MM), uveal and cutaneous melanoma, and other cancers. We demonstrated how germline BAP1 mutations are transmitted over the centuries across generations and f...
Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that arises from the mesothelial surface of the pleural and peritoneal cavities, the pericardium, and rarely, the tunica vaginalis. The incidence of MPM is expected to increase worldwide in the next two decades. However, even with the use of multimodality treatment, MPM remains ch...
Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. While recent epidemiological data demonstrated that the incidence of MPM-related death conti...
We used a custom-made comparative genomic hybridization-array (aCGH; average probe interval 254 bp) to screen 33 malignant mesothelioma (MM) biopsies for somatic copy number loss throughout the 3p21 region (10.7 Mb) that harbors 251 genes, including BRCA1-associated protein 1 (BAP1), the most commonly mutated gene in MM. We identified frequent minu...
Malignant mesothelioma is a very aggressive tumor and has been linked to occupational and environmental exposure to carcinogenic mineral fibers such as asbestos. It was discovered recently that individuals carrying germline BAP1 mutations are predisposed to mesothelioma in presence of even minimal exposure to carcinogenic mineral fibers. Mesothelio...
Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy.
TTK/Mps-1 (monopolar spindle 1 kin...
Carriers of heterozygous germline BAP1 mutations (BAP1+/−) develop cancer. We studied plasma from 16 BAP1+/− individuals from 2 families carrying different germline BAP1 mutations and 30 BAP1 wild-type (BAP1WT) controls from these same families. Plasma samples were analyzed by liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS), ultr...
BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1(+/-)) developed one and often several BAP1(-/-) malignancies in their lifetime, mostly malignant mesothelioma, uveal melanoma, and so on. Moreover, BAP1-a...
A review (in PDF format) of our team’s publications from December 2014 - 2016, describing the research findings. There are links to all of our recent publications directly within the PDF.
Recent discoveries have elucidated some of the mechanisms responsible for the development of mesothelioma. These discoveries are: (I) the critical role of chronic inflammation in promoting mesothelioma growth, driven by the release of high mobility group box protein-1 (HMGB1) following asbestos deposition in tissues and its potential role as a biom...
Malignant mesothelioma (MM) is an aggressive and lethal cancer, mostly related to inhalation of asbestos and erionite fibers. MM is associated with poor prognosis, because of its resistance to current therapies, even if higher survival occurs in patients diagnosed and treated when at stage I of the disease. However, these do not exceed 5% of the to...
Background
Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in...
Human malignant mesothelioma (MM) is an aggressive cancer linked to asbestos and erionite exposure. We previously reported that High-Mobility Group Box-1 protein (HMGB1), a prototypic damage-associated molecular pattern, drives MM development and sustains MM progression. Moreover, we demonstrated that targeting HMGB1 inhibited MM cell growth and mo...
Human malignant mesothelioma (MM) is an aggressive cancer linked to asbestos and erionite exposure. We previously reported that High-Mobility Group Box-1 protein (HMGB1), a prototypic damage-associated molecular pattern, drives MM development and sustains MM progression. Moreover, we demonstrated that targeting HMGB1 inhibited MM cell growth and mo...
Reviewing histologic findings with the aid of a large immunohistochemical panel, we confirmed the diagnosis of MM in 28 patients from ZJCH and 24 from Yuyao People’s Hospital (52 of 92 cases [57%]). The male to female ratio was approximately 1:4 (19%; 95% CI, 10%-32%) compared with 4:1 (80%) in the United States (z = 11.0, P < .001). The pleural to...
Background:
In the Western World malignant mesothelioma (MM) is most prevalent in the pleura of older males professionally exposed to asbestos. Information about MM from rapidly industrializing countries, such as China, is minimal. There is concern that a proportion of MM diagnoses in China may be incorrect because most Chinese physicians do not h...
Significance
We found that gene mutations/deletions are frequent in mesothelioma and occur through a variety of DNA alterations. We identified genes implicated in malignant mesothelioma: SETD2 , SMARCC1 , PBRM1 . Previous next-generation studies (NGS) underestimated the frequency of genetic alterations in malignant mesothelioma because NGS mainly i...
Similar to asbestos fibers, nonregulated mineral fibers can cause malignant mesothelioma (MM). Recently, increased proportions of women and young individuals with MM were identified in southern Nevada, suggesting that environmental exposure to carcinogenic fibers was causing the development of MM. Palygorskite, a fibrous silicate mineral with a his...
Despite predictions of decline in mesothelioma following the ban of asbestos in most industrial countries, the incidence is still increasing globally, particularly in women. Because occupational exposure to asbestos is the main cause of mesothelioma, it occurs four- to eightfold more frequently in men than women, at a median age of 74 years. When m...
Malignant mesothelioma (MM) is an aggressive cancer largely associated with asbestos exposure. In this review, we discuss the significant advancements in our understanding of its genetics and molecular biology and their translational relevance. Remarkable findings included the discovery of germline and somatic mutations of BRCA1-associated protein...
On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant inpu...
Germline BAP1 mutations cause a cancer syndrome characterized by high incidence of mesothelioma (MM), uveal melanoma and other cancers, and by very high penetrance, as all individuals carrying BAP1 mutations developed at least one, and usually several, malignancies throughout their lives. Through screening MM patients with histories of multiple can...
Millions of people have been potentially exposed to asbestos, the primary cause of malignant mesothelioma (MM). Presently, no reliable biomarkers are available to identify among potentially exposed people, those individuals who have actually been exposed and who are at high risk of MM. High Mobility Group Box Protein-1 (HMGB1) is a key mediator of...
The stage I uterine Malignant Mixed Mullerian Tumor (MMMT) shows different potential for progression. We reason that MMMTs with high grade carcinomatous component and positivity for HB-EGF are prone to recurrence/metastasis in the early stage. A retrospective clinical and histopathologic review with immunohistochemical staining for HB-EGF, EGFR, an...