Cloning and expression of the tumor-associated antigen L6.

Marken, John S.; Schieven, Gary L.; Hellström, Ingegerd; Hellström, Karl Erik; Aruffo, Alejandro

doi:10.1073/pnas.89.8.3503

Cited by 123 publications

(101 citation statements)

References 31 publications

(25 reference statements)

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“…Additional genes in this category that have significant implications in cellular migration and invasion include Rho GDP dissociation inhibitor, the thymosin β4 family and the transmembrane 4 superfamily [89][90][91][92]. The urokinase receptor (uPAR), also upregulated in the poorly aggressive melanoma cells exposed to inductive matrices, has been linked to cellular migration through its ability to promote pericellular proteolysis, mediate cell signaling, and regulate integrin function, and most recently has been identified as a preferential binding partner for α3β1 [93,94].…”

Section: Discussionmentioning

confidence: 99%

The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment

Seftor¹,

Meltzer²,

Kirschmann³

et al. 2006

J Cellular Molecular Medi

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Cancer pathogenesis involves dynamic interactions within the tumor-host microenvironment. Most noteworthy is cutaneous melanoma which is considered one of the few remaining cancers escalating in incidence [1,2], and thus represents a growing public health burden worldwide [3; for review, see 4; 5]. In addition, uveal melanoma is considered the most common primary intraocular cancer in adults [6], where metastasis occurs in an unpredictable manner in approximately 50% of patients with a primary tumor originating in the choroid or ciliary body of the eye [6]. Without question, the clinical manage- AbstractA dynamic, complex relationship exists between tumor cells and their microenvironment, which plays a pivotal role in cancer progression, yet remains poorly understood. Particularly perplexing is the finding that aggressive melanoma cells express genes associated with multiple cellular phenotypes, in addition to their ability to form vasculogenic-like networks in three-dimensional matrix -called vasculogenic mimicry, which is illustrative of tumor cell plasticity. This study addressed the unique epigenetic effect of the microenvironment of aggressive melanoma cells on the behavior of poorly aggressive melanoma cells exposed to it. The data show significant changes in the global gene expression of the cells exposed to 3-D matrices preconditioned by aggressive melanoma cells, including the acquisition of a vasculogenic cell phenotype, upregulation of ECM remodeling genes, and increased invasive ability -indicative of an epigenetic, microenvironment-induced reprogramming of poorly aggressive melanoma cells. However, this epigenetic effect was completely abrogated when a highly cross-linked collagen matrix was used, which could not be remodeled by the aggressive melanoma cells. These findings offer an unique perspective of the inductive properties associated with an aggressive melanoma microenvironment that might provide new insights into the epigenetic regulation of tumor cell plasticity and differentiation, as well as mechanisms that could be targeted for novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment

Seftor¹,

Meltzer²,

Kirschmann³

et al. 2006

J Cellular Molecular Medi

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“…This cluster included the epithelial membrane protein EMP1, the connective tissue genes COL14A1, decorin (DCN), elastin (ELN), and the putative elastin associated gene MFAP4 (Zhao et al, 1995). Interestingly, this cluster also included two transmembrane four superfamily proteins, TM4SF1 and TM4SF3, which have been found to be expressed in lung, breast, ovarian, gastric, colon, rectal, and pancreatic tumors, but not in most normal tissues (Szala et al, 1990;Marken et al, 1992). A second cluster of genes that were predictive of T histology were downregulated in T samples and included genes that are involved in cell cycle and proliferation, such as CENPA, CDCA1, CCNB1, CDC20, and MCM5.…”

Section: Differentiation Programs From Classifier Genesmentioning

confidence: 99%

Gene expression-based classification of nonseminomatous male germ cell tumors

et al. 2005

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Male adult germ cell tumors (GCTs) comprise two major histologic groups: seminomas and nonseminomas. Nonseminomatous GCTs (NSGCTs) can be further divided into embryonal carcinoma (EC), teratoma (T), yolk sac tumor (YS), and choriocarcinoma (CC) on the basis of the lineage differentiation that they exhibit. NSGCTs frequently present as mixed tumors consisting of two or more histological subtypes, often limiting correlative studies of clinical and molecular features to histology. We sought to develop a molecular classifier that could predict the predominant histologic subtype within mixed NSGCT tumor samples. The expression profiles of 84 NSGCTs (42 pure and 42 mixed) and normal age-matched testes were obtained using Affymetrix microarrays. Using prediction analysis for microarrays, we identified 146 transcripts that classified the histology of pure NSGCTs samples with 93% accuracy. When applied to mixed NSGCTs, the classifier predicted a histology that was consistent with one of the reported components in 93% of cases. Among the predictive transcripts were CGB (high in CC), LCN2 (high in T), BMP2 (high in YS), and POU5F1 (high in EC). Thus, the expression-based classifier accurately assigned a single predominant histology to mixed NSGCTs, and identified transcripts differentially expressed between histologic components with relevance to NSGCT differentiation.

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“…Tumor cell lines expressing high levels of TM4SF1 were identified with an in silico survey of public and proprietary gene expression databases (CCLE, Oncomine, Gene Logic, and OTP) and from prior publications (7,8,16,37). As a group, NSCLC tumor cell lines expressed the highest levels of TM4SF1 among solid tumors (Fig.…”

Section: Selection Of Tm4sf1-expressing Tumor Cell Linesmentioning

confidence: 99%

“…TM4SF1 is an integral membrane glycoprotein structurally related to tetraspanins (8,9). It is abundantly expressed on many cancer cells (7,10), on endothelial cells lining human cancer blood vessels (11), and on the endothelial cells of angiogenic blood vessels induced in mice with retinopathy of prematurity (12) or by an adenovirus expressing VEGF-A (11).…”

Section: Introductionmentioning

confidence: 99%

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Novel Anti-TM4SF1 Antibody–Drug Conjugates with Activity against Tumor Cells and Tumor Vasculature

Visintin

Knowlton

Tyminski

et al. 2015

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) represent a promising therapeutic modality for managing cancer. Here, we report a novel humanized ADC that targets the tetraspanin-like protein TM4SF1. TM4SF1 is highly expressed on the plasma membranes of many human cancer cells and also on the endothelial cells lining tumor blood vessels. TM4SF1 is internalized upon interaction with antibodies. We hypothesized that an ADC against TM4SF1 would inhibit cancer growth directly by killing cancer cells and indirectly by attacking the tumor vasculature. We generated a humanized anti-human TM4SF1 monoclonal antibody, v1.10, and armed it with an auristatin cytotoxic agent LP2 (chemical name mc-3377). v1.10-LP2 selectively killed cultured human tumor cell lines and human endothelial cells that express TM4SF1. Acting as a single agent, v1.10-LP2 induced complete regression of several TM4SF1-expressing tumor xenografts in nude mice, including non-small cell lung cancer and pancreas, prostate, and colon cancers. As v1.10 did not react with mouse TM4SF1, it could not target the mouse tumor vasculature. Therefore, we generated a surrogate antimouse TM4SF1 antibody, 2A7A, and conjugated it to LP2. At 3 mpk, 2A7A-LP2 regressed several tumor xenografts without noticeable toxicity. Combination therapy with v1.10-LP2 and 2A7A-LP2 together was more effective than either ADC alone. These data provide proof-of-concept that TM4SF1-targeting ADCs have potential as anticancer agents with dual action against tumor cells and the tumor vasculature. Such agents could offer exceptional therapeutic value and warrant further investigation.

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Cloning and expression of the tumor-associated antigen L6.

Cited by 123 publications

References 31 publications

The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment

The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment

Gene expression-based classification of nonseminomatous male germ cell tumors

Novel Anti-TM4SF1 Antibody–Drug Conjugates with Activity against Tumor Cells and Tumor Vasculature

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