Soluble syndecan-1 promotes growth of myeloma tumors in vivo

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 610-617 ◽  
Author(s):  
Yang Yang ◽  
Shmuel Yaccoby ◽  
Wei Liu ◽  
J. Kevin Langford ◽  
Carla Y. Pumphrey ◽  
...  
Keyword(s):  
Cell Surface ◽  
Tumor Cell ◽  
Poor Prognosis ◽  
Lymphoid Cells ◽  
Soluble Form ◽  
Collagen Gels ◽  
Transfected Cells ◽  
Immunodeficient Mice

Abstract Syndecan-1 (CD138) is a transmembrane heparan sulfate–bearing proteoglycan expressed by most myeloma plasma cells that regulates adhesion, migration, and growth factor activity. In patients with myeloma, shed syndecan-1 accumulates in the bone marrow, and high levels of syndecan-1 in the serum are an indicator of poor prognosis. To test the effect of soluble syndecan-1 on tumor cell growth and dissemination, ARH-77 B-lymphoid cells were engineered to produce a soluble form of syndecan-1. Controls included vector only (neo)–transfected cells and cells transfected with full-length syndecan-1 complementary DNA that codes for the cell surface form of syndecan-1. Assays reveal that all 3 transfectants have similar growth rates in vitro, but cells expressing soluble syndecan-1 are hyperinvasive in collagen gels relative to controls. When injected into the marrow of human bones that were implanted in severe combined immunodeficient mice, tumors formed by cells expressing soluble syndecan-1 grow faster than tumors formed by neo-transfected cells or by cells expressing cell surface syndecan-1. In addition, cells bearing cell surface syndecan-1 exhibit a diminished capacity to establish tumors within the mice as compared with both neo- and soluble syndecan-1–transfected cells. Tumor cell dissemination to a contralateral human bone is detected significantly more often in the tumors producing soluble syndecan-1 than in controls. Thus, high levels of soluble syndecan-1 present in patients with myeloma may contribute directly to the growth and dissemination of the malignant cells and thus to poor prognosis.

scholarly journals Induction of Apoptosis of Metastatic Mammary Carcinoma Cells In Vivo by Disruption of Tumor Cell Surface CD44 Function

1997 ◽  
Vol 186 (12) ◽  
pp. 1985-1996 ◽  
Author(s):  
Qin Yu ◽  
Bryan P. Toole ◽  
Ivan Stamenkovic
Keyword(s):  
Cell Surface ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Lung Tissue ◽  
Mammary Carcinoma ◽  
Cell Types ◽  
Pulmonary Endothelium ◽  
Soluble Cd44

To understand how the hyaluronan receptor CD44 regulates tumor metastasis, the murine mammary carcinoma TA3/St, which constitutively expresses cell surface CD44, was transfected with cDNAs encoding soluble isoforms of CD44 and the transfectants (TA3sCD44) were compared with parental cells (transfected with expression vector only) for growth in vivo and in vitro. Local release of soluble CD44 by the transfectants inhibited the ability of endogenous cell surface CD44 to bind and internalize hyaluronan and to mediate TA3 cell invasion of hyaluronan-producing cell monolayers. Mice intravenously injected with parental TA3/St cells developed massive pulmonary metastases within 21–28 d, whereas animals injected with TA3sCD44 cells developed few or no tumors. Tracing of labeled parental and transfectant tumor cells revealed that both cell types initially adhered to pulmonary endothelium and penetrated the interstitial stroma. However, although parental cells were dividing and forming clusters within lung tissue 48 h following injection, >80% of TA3sCD44 cells underwent apoptosis. Although sCD44 transfectants displayed a marked reduction in their ability to internalize and degrade hyaluronan, they elicited abundant local hyaluronan production within invaded lung tissue, comparable to that induced by parental cells. These observations provide direct evidence that cell surface CD44 function promotes tumor cell survival in invaded tissue and that its suppression can induce apoptosis of the invading tumor cells, possibly as a result of impairing their ability to penetrate the host tissue hyaluronan barrier.

scholarly journals Metastatic potential severely altered by changes in tumor cell adhesiveness and cell-surface sialylation.

1983 ◽  
Vol 157 (1) ◽  
pp. 371-376 ◽  
Author(s):  
M Fogel ◽  
P Altevogt ◽  
V Schirrmacher
Keyword(s):  
Sialic Acid ◽  
Cell Surface ◽  
Tumor Cell ◽  
Metastatic Potential ◽  
Lectin Receptors ◽  
Lectin Receptor ◽  
Receptor Sites ◽  
Variant Line

A plastic adherent variant line (ESb-M) of a highly invasive and metastatic murine T cell lymphoma (ESb) was found to have lost its metastatic potential while still being tumorigenic in normal syngeneic hosts. The variant retained most of its ESb-derived antigenic and biochemical characteristics but differed at binding sites for certain lectins with specificity for terminal N-acetylgalactosamine residues. Whereas such sites were masked by sialic acid on metastatic ESb cells, they became unmasked on the adherent variant line. Metastatic revertants of ESb-M cells did not express the respective lectin receptor sites because these were again masked by sialic acid. It is suggested that the masking of specific lectin receptors sites on the tumor cell surface is of crucial importance for metastatis. If freely exposed, these sites may change adherence characteristics of the cells possibly not only in vitro (to plastic) but also in vivo.

scholarly journals LncRNA PVT1 Is a Poor Prognosticator and Can Be Targeted by PVT1 Antisense Oligos in Gastric Adenocarcinoma

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2995
Author(s):  
Yuan Li ◽  
Shumei Song ◽  
Melissa Pool Pizzi ◽  
Guangchun Han ◽  
Ailing W. Scott ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Gastric Adenocarcinoma ◽  
Poor Prognosis ◽  
Survival Duration ◽  
Tumor Cell Growth ◽  
Normal Tissues ◽  
Antisense Oligos

Gastric adenocarcinoma (GAC) is inherently resistant or becomes resistant to therapy, leading to a poor prognosis. Mounting evidence suggests that lncRNAs can be used as predictive markers and therapeutic targets in the right context. In this study, we determined the role of lncRNA-PVT1 in GAC along with the value of inhibition of PVT1 using antisense oligos (ASOs). RNA scope in situ hybridization was used to analyze PVT1 expression in tumor tissue microarrays (TMAs) of GAC and paired normal tissues from 792 patients. Functional experiments, including colony formation and invasion assays, were performed to evaluate the effects of PVT1 ASO inhibition of PVT1 in vitro; patient-derived xenograft models were used to evaluate the anti-tumor effects of PVT1 ASOs in vivo. LncRNA-PVT1 was upregulated in GACs compared to the matched adjacent normal tissues in the TMA. LncRNA PVT1 expression was positively correlated with larger tumor size, deeper wall invasion, lymph node metastases, and short survival duration. Inhibition of PVT1 using PVT1 ASOs significantly suppressed tumor cell growth and invasion in vitro and in vivo. PVT1 expression was highly associated with poor prognosis in GAC patients and targeting PVT1 using PVT1 ASOs was effective at curtailing tumor cell growth in vitro and in vivo. Thus, PVT1 is a poor prognosticator as well as therapeutic target. Targeting PVT1 using PVT1 ASOs provides a novel therapeutic strategy for GAC.

scholarly journals Manganese systemic distribution is modulated in vivo during tumor progression and affects tumor cell migration and invasion in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mariana Paranhos Stelling ◽  
Mariana Alves Soares ◽  
Simone Coutinho Cardoso ◽  
Juliana Maria Motta ◽  
Joice Côrtes de Abreu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Tumor Progression ◽  
Common Ground ◽  
Central Element ◽  
Soluble Form ◽  
Migration And Invasion ◽  
Primary Tumors

AbstractMetastatic disease remains the leading cause of death in cancer and understanding the mechanisms involved in tumor progression continues to be challenging. This work investigates the role of manganese in tumor progression in an in vivo model of tumor growth. Our data revealed that manganese accumulates within primary tumors and secondary organs as manganese-rich niches. Consequences of such phenomenon were investigated, and we verified that short-term changes in manganese alter cell surface molecules syndecan-1 and β1-integrin, enhance collective cell migration and invasive behavior. Long-term increased levels of manganese do not affect cell growth and viability but enhance cell migration. We also observed that manganese is secreted from tumor cells in extracellular vesicles, rather than in soluble form. Finally, we describe exogenous glycosaminoglycans that counteract manganese effects on tumor cell behavior. In conclusion, our analyses describe manganese as a central element in tumor progression by accumulating in Mn-rich niches in vivo, as well as in vitro, affecting migration and extracellular vesicle secretion in vitro. Manganese accumulation in specific regions of the organism may not be a common ground for all cancers, nevertheless, it represents a new aspect of tumor progression that deserves special attention.

scholarly journals Cancer-Associated Mutations Reveal a Novel Role for EpCAM as an Inhibitor of Cathepsin-L and Tumor Cell Invasion

2020 ◽  
Author(s):  
Narendra Sankpal ◽  
Taylor C. Brown ◽  
Timothy P. Fleming ◽  
John M. Herndon ◽  
Anusha A. Amaravati ◽  
...  
Keyword(s):  
Cell Surface ◽  
Tumor Cell ◽  
Cell Invasion ◽  
Cancer Biology ◽  
Human Cancer ◽  
Cathepsin L ◽  
Surface Expression ◽  
Tumor Cell Invasion

Abstract BackgroundEpithelial cell adhesion molecule (EpCAM) is a 40-kD type-I transmembrane protein that is frequently overexpressed in human epithelial cancers. Recent evidence implicates EpCAM in the regulation of oncogenic signaling pathways and epithelial-mesenchymal transition. Of note, multiple proteins with thyroglobulin-type-1 (TY-1) domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor invasion and metastasis.MethodsHuman cancer sequencing studies reveal that somatic EpCAM mutations are present in up to 5.1% of tested tumors form public database search. To determine how EpCAM mutations affect cancer biology we studied C66Y, a damaging TY-1 domain mutation identified in liver cancer, as well as 13 other cancer-associated EpCAM mutations. Using in-vitro and in-vivo models, immunoprecipitations and localizations we demonstrate EpCAM inhibits CTSL activity based mutations and thereby its localization.ResultsWe demonstrate that wild type (WT) EpCAM, but not C66Y EpCAM, inhibits CTSL activity in vitro, and the TY-1 domain of EpCAM is responsible for this inhibition. WT EpCAM, but not C66Y EpCAM, inhibits tumor cell invasion in vitro and lung metastasis in vivo. In an extended panel of human cancer cell lines, EpCAM expression is inversely correlated with CTSL activity. Previous studies have demonstrated that EpCAM germline mutations can prevent EpCAM from being expressed at the cell surface. We demonstrate that C66Y and multiple other EpCAM cancer-associated mutations prevent surface expression of EpCAM. Cancer-associated mutations that prevent EpCAM cell surface expression abrogate the ability of EpCAM to inhibit CTSL activity and tumor cell invasion. ConclusionsThese studies reveal a novel role for EpCAM as a CTSL inhibitor, confirm the functional relevance of multiple cancer-associated EpCAM mutations, and suggest a therapeutic vulnerability in cancers harboring EpCAM mutations.

scholarly journals In Vivo Overexpression of IL-13 Receptor α2 Chain Inhibits Tumorigenicity of Human Breast and Pancreatic Tumors in Immunodeficient Mice

2001 ◽  
Vol 194 (12) ◽  
pp. 1743-1754 ◽  
Author(s):  
Koji Kawakami ◽  
Mariko Kawakami ◽  
Philip J. Snoy ◽  
Syed R. Husain ◽  
Raj K. Puri
Keyword(s):  
Cell Lines ◽  
Inflammatory Cells ◽  
Pancreatic Tumors ◽  
Tumor Cell Lines ◽  
Human Breast ◽  
Transfected Cells ◽  
Immunodeficient Mice ◽  
Receptor Chain

Interleukin 13 receptor α2 (IL-13Rα2) chain is highly expressed on some tumor cell lines and primary cell cultures. This receptor chain plays an important role in ligand binding and internalization. To determine the functional significance of overexpression of this chain, we stably transfected IL-13Rα2 chain in human breast (MDA-MB-231) and pancreatic (PANC-1) cancer cell lines that naturally do not express this chain. There was no difference in growth between vector only transfected and IL-13Rα2 chain transfected cells in vitro. However, surprisingly, in immunodeficient mice, tumorigenicity was profoundly inhibited in IL-13Rα2 chain overexpressing tumors. Because breast tumors that grew later showed loss of IL-13Rα2 gene expression, lack of tumorigenicity correlated positively with IL-13Rα2 chain expression. Inflammatory cells including neutrophils and macrophages were identified in IL-13Rα2 overexpressing regressing tumors and neutrophils were found to produce IL-13. IL-13 showed a modest antitumor activity to IL-13Rα2 chain overexpressing tumors in vitro and in vivo. Furthermore, IL-13Rα2 chain overexpressing tumors constitutively produced IL-8 that has been shown to have antitumor effect. These results establish a novel function of a cytokine receptor chain and further suggest that the presence of this chain on tumor cells by itself may play a key role in tumorigenicity.

Alien Histocompatibility Determinants on the Cell Surface of Sarcomas Induced by Methylcholanthrene. II. in Vitro Serological Studies

1977 ◽  
Vol 63 (2) ◽  
pp. 181-194 ◽  
Author(s):  
Giovanni Invernizzi ◽  
Giusi Carbone ◽  
Giorgio Parmiani
Keyword(s):  
Cell Surface ◽  
Binding Activity ◽  
Lymphoid Cells ◽  
Normal Cells ◽  
Cross Reactions ◽  
Complement Dependent Cytotoxicity ◽  
Antiglobulin Test ◽  
Serological Studies

In vitro serological studies were carried out in an attempt to identify the foreign histocompatibility antigens previously detected by transplantation methods on the cell surface of 2 methylcholanthrene-induced BALB/c fibrosarcomas (TZ15 and ST2). The reactivity of the anti-TZ15 and anti-ST2 syngeneic sera and of the C57BL/6J anti-TZ15 and anti-ST2 sera (the latters preabsorbed on normal BALB/c lymphoid cells) was evaluated on normal lymph node cells of C3Hf, C57BL/6J, DBA/2 and AKR strains by the complement-dependent cytotoxicity and on normal fibroblasts of C3Hf and C57BL/6J mice by the isotopic antiglobulin assay. The ability of in vitro-plated TZ15 and ST2 cells to bind BALB/c anti-C3Hf, anti-C57BL/6J, anti-AKR and anti-DBA/2 alloantisera was also examined by the antiglobulin assay. Contrary to the in vivo data, no cross-reactions were found between TZ15 and AKR normal cells, since both syngeneic and allogeneic anti-TZ15 sera were not cytotoxic to C3Hf, C57BL/6J or AKR lymphoid cells nor could BALB/c anti-C3Hf, anti-C57BL/6J or anti-AKR sera bind to TZ15 tumor cells in the antiglobulin assay. Both BALB/c anti-ST2 and C57BL/6J anti-ST2 sera were also ineffective in killing normal C3Hf, C57BL/6J, AKR and DBA/2 lymphoid cells in the complement–dependent cytotoxic assay, whereas a weak but significant binding of the syngeneic anti-ST2 serum to C57BL/6J but not to C3Hf fibroblasts was detected by the antiglobulin test. ST2 but not TZ15 cells were also able to significantly absorb the complement–dependent cytotoxic activity of a BALB/c anti-C57BL/6J but not of a BALB/c anti-C3Hf antiserum. In addition, BALB/c anti-C3Hf, anti-C57BL/6J and anti-AKR sera but not BALB/c anti-DBA/2 serum strongly bound to ST2 cells in the antiglobulin test; this binding activity was absorbed by C3Hf, C57BL/6J, AKR, and NIH but not BALB/c and DBA/2 lymphoid cells. Thus, among the cross-reactions observed in vivo between ST2 and normal cells of C3Hf, DBA/2 and C57BL/6J strains, only C57BL/6J normal antigens were detectable by serology. A new but still undefined system of alien normal antigens shared by C3Hf, AKR, C57BL/6J, NIH lymphoid and ST2 cells was revealed by the BALB/c alloantisera in the antiglobulin assay. The relationship of these findings with those previously obtained in the transplantation study with the same tumors is discussed.

scholarly journals Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Narendra V. Sankpal ◽  
Taylor C. Brown ◽  
Timothy P. Fleming ◽  
John M. Herndon ◽  
Anusha A. Amaravati ◽  
...  
Keyword(s):  
Cell Surface ◽  
Tumor Cell ◽  
Cell Invasion ◽  
Human Cancer ◽  
Cathepsin L ◽  
Surface Expression ◽  
Tumor Cell Invasion ◽  
In Vivo Models

Abstract Background EpCAM (Epithelial cell adhesion molecule) is often dysregulated in epithelial cancers. Prior studies implicate EpCAM in the regulation of oncogenic signaling pathways and epithelial-to-mesenchymal transition. It was recently demonstrated that EpCAM contains a thyroglobulin type-1 (TY-1) domain. Multiple proteins with TY-1 domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor cell invasion and metastasis. Analysis of human cancer sequencing studies reveals that somatic EpCAM mutations are present in up to 5.1% of tested tumors. Methods The Catalogue of Somatic Mutations in Cancer (COSMIC) database was queried to tabulate the position and amino acid changes of cancer associated EpCAM mutations. To determine how EpCAM mutations affect cancer biology we studied C66Y, a damaging TY-1 domain mutation identified in liver cancer, as well as 13 other cancer-associated EpCAM mutations. In vitro and in vivo models were used to determine the effect of wild type (WT) and mutant EpCAM on CTSL activity and invasion. Immunoprecipitation and localization studies tested EpCAM and CTSL protein binding and determined compartmental expression patterns of EpCAM mutants. Results We demonstrate that WT EpCAM, but not C66Y EpCAM, inhibits CTSL activity in vitro, and the TY-1 domain of EpCAM is responsible for this inhibition. WT EpCAM, but not C66Y EpCAM, inhibits tumor cell invasion in vitro and lung metastases in vivo. In an extended panel of human cancer cell lines, EpCAM expression is inversely correlated with CTSL activity. Previous studies have demonstrated that EpCAM germline mutations can prevent EpCAM from being expressed at the cell surface. We demonstrate that C66Y and multiple other EpCAM cancer-associated mutations prevent surface expression of EpCAM. Cancer-associated mutations that prevent EpCAM cell surface expression abrogate the ability of EpCAM to inhibit CTSL activity and tumor cell invasion. Conclusions These studies reveal a novel role for EpCAM as a CTSL inhibitor, confirm the functional relevance of multiple cancer-associated EpCAM mutations, and suggest a therapeutic vulnerability in cancers harboring EpCAM mutations.

A Molecular Approach to Immunoscintigraphy: A Study of the T-Antigen Conformation on the Surface of Tumors

1987 ◽  
Vol 26 (01) ◽  
pp. 1-6 ◽  
Author(s):  
S. Selvaraj ◽  
M. R. Suresh ◽  
G. McLean ◽  
D. Willans ◽  
C. Turner ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Cell ◽  
T Antigen ◽  
Human Carcinomas ◽  
Animal Tumor ◽  
Synthetic Antigens

The role of glycoconjugates in tumor cell differentiation has been well documented. We have examined the expression of the two anomers of the Thomsen-Friedenreich antigen on the surface of human, canine and murine tumor cell membranes both in vitro and in vivo. This has been accomplished through the synthesis of the disaccharide terminal residues in both a and ß configuration. Both entities were used to generate murine monoclonal antibodies which recognized the carbohydrate determinants. The determination of fine specificities of these antibodies was effected by means of cellular uptake, immunohistopathology and immunoscintigraphy. Examination of pathological specimens of human and canine tumor tissue indicated that the expressed antigen was in the β configuration. More than 89% of all human carcinomas tested expressed the antigen in the above anomeric form. The combination of synthetic antigens and monoclonal antibodies raised specifically against them provide us with invaluable tools for the study of tumor marker expression in humans and their respective animal tumor models.

scholarly journals Aberrantly high activation of a FoxM1–STMN1 axis contributes to progression and tumorigenesis in FoxM1-driven cancers

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jun Liu ◽  
Jipeng Li ◽  
Ke Wang ◽  
Haiming Liu ◽  
Jianyong Sun ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Poor Prognosis ◽  
Soft Agar ◽  
Transcriptional Level ◽  
Regulation Mechanism ◽  
Strong Positive Correlation ◽  
Cell Viability Assay ◽  
High Level

AbstractFork-head box protein M1 (FoxM1) is a transcriptional factor which plays critical roles in cancer development and progression. However, the general regulatory mechanism of FoxM1 is still limited. STMN1 is a microtubule-binding protein which can inhibit the assembly of microtubule dimer or promote depolymerization of microtubules. It was reported as a major responsive factor of paclitaxel resistance for clinical chemotherapy of tumor patients. But the function of abnormally high level of STMN1 and its regulation mechanism in cancer cells remain unclear. In this study, we used public database and tissue microarrays to analyze the expression pattern of FoxM1 and STMN1 and found a strong positive correlation between FoxM1 and STMN1 in multiple types of cancer. Lentivirus-mediated FoxM1/STMN1-knockdown cell lines were established to study the function of FoxM1/STMN1 by performing cell viability assay, plate clone formation assay, soft agar assay in vitro and xenograft mouse model in vivo. Our results showed that FoxM1 promotes cell proliferation by upregulating STMN1. Further ChIP assay showed that FoxM1 upregulates STMN1 in a transcriptional level. Prognostic analysis showed that a high level of FoxM1 and STMN1 is related to poor prognosis in solid tumors. Moreover, a high co-expression of FoxM1 and STMN1 has a more significant correlation with poor prognosis. Our findings suggest that a general FoxM1-STMN1 axis contributes to cell proliferation and tumorigenesis in hepatocellular carcinoma, gastric cancer and colorectal cancer. The combination of FoxM1 and STMN1 can be a more precise biomarker for prognostic prediction.

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