Cytopathology of malignant mesothelioma. Reappraisal of the diagnostic value of collagen cores

Delahaye, Mick; Jong, A.A.W. de; Versnel, M. A.; Hoogsteden, H. C.; Teeling, Peter; Kwast, T. H. Van Der

doi:10.1111/j.1365-2303.1990.tb00339.x

Cited by 17 publications

(12 citation statements)

References 13 publications

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“…Fragments of tumor found in cytologic preparations of malignant pleural fluid are strongly associated with malignancy, and are much more frequently found in mesothelioma than in adenocarcinoma. These fragments often have an internal structure composed of collagen called a collagen core that, in one study, was found in 64% of mesothelioma cases versus 4% of adenocarcinoma cases (34). The source of these fragmentary tumor structures is unknown, but is speculated to be due to shedding of tumor cells or breakage of papillary structures.…”

Section: Discussionmentioning

confidence: 99%

A Novel In Vitro Model of Human Mesothelioma for Studying Tumor Biology and Apoptotic Resistance

Kim

Wilson²,

Abayasiriwardana³

et al. 2005

Am J Respir Cell Mol Biol

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Like many tumors, malignant mesothelioma exhibits significant chemoresistance and resistance to apoptosis in vivo that is not seen in current in vitro models. To study the mechanisms of this multicellular resistance, biologically relevant in vitro models are necessary. Therefore, we characterized and tested human mesothelioma tissue grown in vitro as tumor fragment spheroids. After 5-10 d in culture, fragments from each of 15 human mesothelioma tumors rounded into spheroids. The tumor fragment spheroids maintained multiple characteristics of the original tumors for up to 3 mo including the presence of viable mesothelioma cells, macrophages, and a collagenrich stroma. In 14-d-old spheroids, mesothelioma cells showed the same proliferation rate and expression of a death receptor, DR5, as in the original tumor. To determine responses to treatment, we treated tumor fragment spheroids grown from three separate tumors with agents, TNF-related apoptosis-inducing ligand (TRAIL) plus cycloheximide, that induced near total apoptosis in three human mesothelioma cell lines (M28, REN, MS-1) grown as monolayers (94 Ϯ 6% apoptosis; mean Ϯ SEM). Compared with mesothelioma cells in monolayers, mesothelioma cells in the spheroids were resistant to TRAIL plus cycloheximide (32 Ϯ 4% apoptosis; mean Ϯ SEM). Apoptotic resistance of mesothelioma cells was significantly reduced by inhibiting either the PI3K/Akt pathway with LY294002 (47 Ϯ 6% apoptosis) or the mTOR pathway with rapamycin (50 Ϯ 17% apoptosis). We conclude that human mesothelioma can be maintained in vitro in a biologically relevant model that exhibits apoptotic resistance, thereby permitting study of its tumor biology and of novel approaches to therapy. Keywords: collagen; death receptor DR5; mTOR; multicellular resistance; PI3K/Akt survival pathway; TNF-related apoptosis-inducing ligand (TRAIL); tumor-associated macrophage; tumor fragment spheroid Resistance to apoptosis, or programmed cell death, is now considered to be a critical step in the generation and maintenance of cancer (1). Resistance to apoptosis may underlie the resistance of tumors to chemotherapy and radiotherapy (2). Mechanisms of resistance have been identified on a cellular level, for example via P-glycoprotein efflux pumps, DNA repair mechanisms, or from expression of anti-apoptotic proteins such as Bcl-2 (3). Additional mechanisms of resistance are now recognized to involve stimuli from the cell's external environment, termed multicellular resistance (3). These multicellular resistance mechanisms have been attributed to cell-cell contacts, cell-matrix contacts, and the three-dimensional shape found in tissues but (Received in original form November 14, 2004 and in final form July 30, 2005) *These authors contributed equally to this work. Two types of in vitro models used to study the complex resistance found in tumors are multicellular spheroids and tumor fragment spheroids (5, 6). In the first, cells are allowed to grow into three-dimensional structures called multicellular spheroids (5). In thes...

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Section: Discussionmentioning

confidence: 99%

A Novel In Vitro Model of Human Mesothelioma for Studying Tumor Biology and Apoptotic Resistance

Kim

Wilson²,

Abayasiriwardana³

et al. 2005

Am J Respir Cell Mol Biol

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“…Malignant mesothelioma, a tumor extremely resistant to chemotherapy, seems well suited for this approach: surgical resection generally provides a large amount of tumor that can be studied ex vivo, and mesothelioma is known to form spheroidal aggregates in vivo (27). Novel approaches in preclinical studies are also attractive for mesothelioma because it is a relatively uncommon tumor, thereby slowing accrual into clinical trials.…”

Section: Discussionmentioning

confidence: 99%

mTOR Mediates Survival Signals in Malignant Mesothelioma Grown as Tumor Fragment Spheroids

Wilson¹,

Barbone²,

Yang³

et al. 2008

Am J Respir Cell Mol Biol

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“…It is not clear whether there is a degeneration or an anomalous production of this type of collagen which is also present in MS and EDS. In conclusion, we suspect that collagen [25, 26, 27, 28]may play a role in both these two syndromes and mesothelioma.…”

Section: Discussionmentioning

confidence: 99%

Malignant Mesothelioma in Subjects with Marfan’s Syndrome and Ehlers-Danlos Syndrome: Only an Apparent Association?

Bisconti¹,

Bisetti²,

Bidoli³

2000

Respiration

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Malignant mesothelioma is a rare neoplasm which could be favored by an hereditary predisposing factor. So far, malignant mesothelioma have never been described in patients with hereditary diseases of the connective tissue. Here, we report some cases of mesothelioma affecting subjects who were not exposed to inhalation of asbestos. One of these subjects was affected by Ehlers-Danlos syndrome, whereas in two brothers, mesothelioma was associated with Marfan’s syndrome. The observation of the same histologic subtype of mesothelioma in two brothers and the coexistence of two pathologic conditions of mesodermal origin indicate the presence of hereditary factors predisposing to the cancerogenic action of even small amounts of asbestos. Structural alterations of collagen and primary immunodeficiency may represent the host factor inducing development of the neoplasm. We conclude that the association between these rare disorders of the connective tissue and mesothelioma may not be coincidental, but could be the result of the exposition to small amounts of asbestos in predisposed individuals.

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Cytopathology of malignant mesothelioma. Reappraisal of the diagnostic value of collagen cores

Cited by 17 publications

References 13 publications

A Novel In Vitro Model of Human Mesothelioma for Studying Tumor Biology and Apoptotic Resistance

A Novel In Vitro Model of Human Mesothelioma for Studying Tumor Biology and Apoptotic Resistance

mTOR Mediates Survival Signals in Malignant Mesothelioma Grown as Tumor Fragment Spheroids

Malignant Mesothelioma in Subjects with Marfan’s Syndrome and Ehlers-Danlos Syndrome: Only an Apparent Association?

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