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1

Article

Cancer-Associated Fibroblasts Share Characteristics and Protumorigenic Activity with Mesenchymal Stromal Cells

Borriello, Lucia ; Nakata, Rie ; Sheard, Michael A ; [et al.]

2017

ISSN: 0008-5472

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Language: English

In: Cancer research (Chicago, Ill.), 2017-09-15, Vol.77 (18), p.5142-5157

Description: Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship with MSCs is not clear. Here, we have isolated from primary human neuroblastoma tumors a population of αFAP- and FSP-1-expressing CAFs that share phenotypic and functional characteristics with bone marrow-derived MSCs (BM-MSC). Analysis of human neuroblastoma tumors also confirmed the presence of αFAP- and FSP-1-positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSCs) enhanced neuroblastoma cell proliferation, survival, and resistance to chemotherapy and stimulated neuroblastoma tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The protumorigenic activity of MSCs and in xenografted mice was dependent on the coactivation of JAK2/STAT3 and MEK/ERK1/2 in neuroblastoma cells. In a mouse model of orthotopically implanted neuroblastoma cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type of protumorigenic CAF in the tumor microenvironment of neuroblastoma and to STAT3 and ERK1/2 as mediators of their activity. .

Subject(s): Apoptosis - drug effects ; Cancer-Associated Fibroblasts - metabolism ; Humans ; Cancer-Associated Fibroblasts - drug effects ; Culture Media, Conditioned - pharmacology ; Male ; Janus Kinase 2 - metabolism ; Biomarkers, Tumor - metabolism ; Bone Marrow Cells - drug effects ; Female ; Pyrimidinones - pharmacology ; Antineoplastic Agents - pharmacology ; Gene Expression Regulation, Neoplastic - drug effects ; Tumor Cells, Cultured ; Neuroblastoma - pathology ; STAT3 Transcription Factor - metabolism ; Pyrazoles - pharmacology ; Tumor Microenvironment - drug effects ; Mesenchymal Stromal Cells - drug effects ; Bone Marrow Cells - pathology ; Mesenchymal Stromal Cells - metabolism ; MAP Kinase Kinase 1 - metabolism ; Mice, SCID ; Xenograft Model Antitumor Assays ; Cancer-Associated Fibroblasts - pathology ; Animals ; Mitogen-Activated Protein Kinase 3 - metabolism ; Cell Differentiation - drug effects ; Neuroblastoma - drug therapy ; Mice, Inbred NOD ; Cell Proliferation - drug effects ; Mice ; Neuroblastoma - metabolism ; Mesenchymal Stromal Cells - pathology ; Bone Marrow Cells - metabolism ; Pyridones - pharmacology ; Mitogen-Activated Protein Kinase 1 - metabolism ; Index Medicus

ISSN: 0008-5472

E-ISSN: 1538-7445

DOI: 10.1158/0008-5472.CAN-16-2586

Source: HighWire Press (Free Journals)

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2

Article

A prospective, observational cohort study comparing cancer clinical trial availability and enrollment between early adolescents/young adults and children

Thomas, Stefanie M ; Malvar, Jemily ; Tran, Henry ; [et al.]

2018

ISSN: 0008-543X

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Language: English

In: Cancer, 2018-03-01, Vol.124 (5), p.983-990

Description: BACKGROUND Poor enrollment of adolescents and young adults (AYAs) (ages 15‐39 years) onto cancer clinical trials (CCTs) may contribute to inferior survival gains compared with children. In this study, the authors assessed whether differences in CCT availability would explain lower CCT enrollment for early AYAs (eAYAs) (ages 15‐21 years). METHODS This prospective, observational cohort study was conducted at a single academic children's hospital. For consecutive patients who were newly diagnosed with cancer over a 13‐month period, it was determined whether an appropriate CCT existed nationally or was available locally and whether enrollment on that CCT occurred. The proportions of eAYAs versus children in each category were compared using the chi‐square test. The impact of age and other factors on enrollment status was assessed using logistic regression analysis. RESULTS Among 216 patients, 58 were eAYAs, and 158 were children. There was no difference in the proportion of eAYAs versus children who had an existing CCT (28 of 58 eAYAs [48.3%] vs 85 of 158 children [53.8%]; P = .47) or an available CCT (23 of 58 eAYAs [39.7%] vs 75 of 158 children [47.5%]; P = .31). However, significantly fewer eAYAs were enrolled when a CCT was available (7 of 23 eAYAs [30.4%] vs 50 of 75 children [67.7%]; P = .002). In multivariable analysis, eAYAs were significantly less likely than children to be enrolled in an available CCT (adjusted odds ratio, 0.22; 95% confidence interval, 0.08‐0.62). CONCLUSIONS Equal proportions of children and eAYAs had CCTs available, but significantly fewer eAYAs were enrolled. These findings suggest that, for eAYAs, factors other than CCT availability are important enrollment barriers and should be addressed. Cancer 2018;124:983‐90. © 2017 American Cancer Society. In this case‐linked, prospective study, no difference is observed in cancer clinical trial availability for newly diagnosed children and early adolescents/young adults, but a significantly lower proportion of early adolescents/young adults are enrolled onto cancer clinical trials when available.

Subject(s): adolescent ; young adult ; clinical oncology ; clinical trial as topic ; Care and treatment ; Cohort analysis ; Usage ; Young adults ; Clinical trials ; Research ; Health aspects ; Risk factors ; Cancer ; Young Adult ; Clinical Oncology ; Adolescent ; Clinical Trial as Topic

ISSN: 0008-543X

E-ISSN: 1097-0142

DOI: 10.1002/cncr.31127

Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

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3

Article

TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells

Tran, Hung C ; Wan, Zesheng ; Sheard, Michael A ; [et al.]

2017

ISSN: 1078-0432

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Language: English

In: Clinical cancer research, 2017-02-01, Vol.23 (3), p.804-813

Description: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by neuroblastoma patient blood and bone marrow plasmas in neuroblastoma cells was tested. The impact of galunisertib on TGFβ1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NOD-scid gamma (NSG) mice was determined. Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors and the TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against neuroblastoma cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two neuroblastoma cell lines or a patient-derived xenograft. Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors. Clin Cancer Res; 23(3); 804-13. ©2016 AACRSee related commentary by Zenarruzabeitia et al., p. 615.

Subject(s): Receptor, Transforming Growth Factor-beta Type I ; Receptors, Transforming Growth Factor beta - genetics ; Humans ; Neoplasm Proteins - physiology ; Male ; Neoplasm Proteins - antagonists & inhibitors ; Gene Expression Profiling ; Receptors, Transforming Growth Factor beta - physiology ; Smad2 Protein - antagonists & inhibitors ; Quinolines - pharmacology ; RNA, Messenger - biosynthesis ; Protein Processing, Post-Translational - drug effects ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Female ; Phosphorylation - drug effects ; Neuroblastoma - pathology ; Transforming Growth Factor beta1 - biosynthesis ; Pyrazoles - pharmacology ; Killer Cells, Natural - transplantation ; Specific Pathogen-Free Organisms ; Immunotherapy, Adoptive ; Protein-Serine-Threonine Kinases - physiology ; Antibodies, Monoclonal - pharmacology ; RNA, Messenger - genetics ; Protein-Serine-Threonine Kinases - genetics ; Smad2 Protein - metabolism ; Transforming Growth Factor beta1 - genetics ; Transforming Growth Factor beta1 - physiology ; Antineoplastic Agents, Immunological - pharmacology ; Drug Synergism ; Protein-Serine-Threonine Kinases - biosynthesis ; Xenograft Model Antitumor Assays ; Receptors, Transforming Growth Factor beta - biosynthesis ; Animals ; RNA, Neoplasm - biosynthesis ; Receptors, Transforming Growth Factor beta - antagonists & inhibitors ; Cell Line, Tumor ; RNA, Neoplasm - genetics ; Mice, Inbred NOD ; Mice ; Neuroblastoma - metabolism ; Cytotoxicity, Immunologic ; Index Medicus ; TGFβR1 inhibitor ; dinutuximab ; adoptive cell therapy ; galunisertib ; immunotherapy

ISSN: 1078-0432

E-ISSN: 1557-3265

DOI: 10.1158/1078-0432.CCR-16-1743

Source: HighWire Press (Free Journals)

Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

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4

Article

A prospective comparison of cancer clinical trial availability and enrollment among adolescents/young adults treated at an adult cancer hospital or affiliated children’s hospital

Thomas, Stefanie M ; Malvar, Jemily ; Tran, Hanh Henry ; [et al.]

2018

ISSN: 0008-543X

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Language: English

In: Cancer, 2018-10-15, Vol.124 (20), p.4064-4071

Description: Background Low cancer clinical trial (CCT) enrollment may contribute to survival disparities affecting adolescents and young adults (AYAs) (ages 15‐39 years). The objective of this study was to evaluate whether differences in CCT availability related to treatment site could explain the low CCT enrollment. Methods This prospective, observational cohort study was conducted at an academic children’s hospital and its affiliated but geographically separated adult cancer hospital within a National Cancer Institute‐designated Comprehensive Cancer Center. For consecutive, newly diagnosed AYA patients, it was determined whether an appropriate CCT existed nationally, was available at the treatment site, and was used for enrollment. Proportions of AYAs in these categories were compared between sites using the chi‐square test. Results One hundred fifty‐two consecutive AYA patients were included from the children’s hospital (n = 68; ages 15‐20 years) and the adult cancer hospital (n = 84; ages 18‐39 years). Although there was no difference in CCT existence for individual AYA patients by site (children’s hospital [36 of 68 patients; 52.9%] vs adult cancer hospital [45 of 84 patients; 53.6%]; P = .938), CCT availability was significantly lower at the adult cancer hospital (14 of 84 patients [16.7%] vs 30 of 68 [44.1%] at the children’s hospital; P 〈 .001). The proportion of AYAs enrolled was low at both sites (8 of 68 patients [11.8%] vs 6 of 84 patients [7.1%], respectively; P = .327). Fewer existing CCTs were available at the adult cancer hospital (4 of 27 patients [14.8%] vs 8 of 14 patients [57.1%], respectively), and those were directed toward solid tumors and new agents. Conclusions Efforts to improve low CCT enrollment among AYAs should be differentiated by treatment site. In the adult setting, these efforts should be aimed at improving CCT availability by overcoming site‐level barriers to opening existing CCTs. In this prospective study, clinical trial enrollment is compared between adolescents/young adults (AYAs) (ages 15‐39 years) treated at either a children’s hospital or at its affiliated adult cancer hospital. Although the existence of cancer clinical trials (CCTs) is similar nationally, significantly fewer AYAs at adult sites have an available CCT, and the major implication of this finding is that efforts to improve low CCT enrollment among AYAs must be differentiated by site and, in the adult setting, should be aimed at overcoming institution‐level barriers to opening existing CCTs. See also pages 3965‐8 and 4098‐106.

Subject(s): adolescents and young adults (AYAs) ; multicenter studies as topic ; pediatric oncology ; adolescent ; young adult ; clinical oncology ; clinical trial as topic ; Index Medicus ; Abridged Index Medicus ; Young Adult ; Pediatric Oncology ; Multicenter Studies as Topic ; Adolescent ; Clinical Oncology ; AYA ; Clinical Trial as Topic

ISSN: 0008-543X

E-ISSN: 1097-0142

DOI: 10.1002/cncr.31727

Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

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5

Article

Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes

Webb, Matthew W ; Sun, Jianping ; Sheard, Michael A ; [et al.]

2018

ISSN: 0020-7136

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Language: English

In: International journal of cancer, 2018-09-15, Vol.143 (6), p.1483-1493

Description: Tumor‐associated macrophages can promote growth of cancers. In neuroblastoma, tumor‐associated macrophages have greater frequency in metastatic versus loco‐regional tumors, and higher expression of genes associated with macrophages helps to predict poor prognosis in the 60% of high‐risk patients who have MYCN‐non‐amplified disease. The contribution of cytotoxic T‐lymphocytes to anti‐neuroblastoma immune responses may be limited by low MHC class I expression and low exonic mutation frequency. Therefore, we modelled human neuroblastoma in T‐cell deficient mice to examine whether depletion of monocytes/macrophages from the neuroblastoma microenvironment by blockade of CSF‐1R can improve the response to chemotherapy. In vitro, CSF‐1 was released by neuroblastoma cells, and topotecan increased this release. In vivo, neuroblastomas formed by subcutaneous co‐injection of human neuroblastoma cells and human monocytes into immunodeficient NOD/SCID mice had fewer human CD14+ and CD163+ cells and mouse F4/80+ cells after CSF‐1R blockade. In subcutaneous or intra‐renal models in immunodeficient NSG or NOD/SCID mice, CSF‐1R blockade alone did not affect tumor growth or mouse survival. However, when combined with cyclophosphamide plus topotecan, the CSF‐1R inhibitor BLZ945, either without or with anti‐human and anti‐mouse CSF‐1 mAbs, inhibited neuroblastoma growth and synergistically improved mouse survival. These findings indicate that depletion of tumor‐associated macrophages from neuroblastomas can be associated with increased chemotherapeutic efficacy without requiring a contribution from T‐lymphocytes, suggesting the possibility that combination of CSF‐1R blockade with chemotherapy might be effective in patients who have limited anti‐tumor T‐cell responses. What's new? Monocytes and macrophages rely on colony stimulating factor‐1 (CSF‐1) and its receptor, CSF‐1R, for recruitment and survival in the tumor microenvironment. Moreover, CSF‐1 expression is associated with poor prognosis in certain cancer types. This work shows that after treatment with the chemotherapeutic agent topotecan, neuroblastoma cells increase CSF‐1 release. In immunodeficient mice with neuroblastomas induced by co‐injection of human neuroblastoma cells and human monocytes, BLZ945, a small molecule inhibitor of CSF‐1R, enhanced the chemotherapeutic effects, inhibiting neuroblastoma growth and improving survival. The findings could have implications for the treatment of neuroblastoma and other cancers with limited cancer‐fighting T‐lymphocyte responses.

Subject(s): neuroblastoma ; tumor‐associated macrophage ; MCS110 ; BLZ945 ; 5A1 ; Chemotherapy ; Neuroblastoma ; T cells ; Macrophages ; Analysis ; Cancer ; Index Medicus ; tumor-associated macrophage

ISSN: 0020-7136

E-ISSN: 1097-0215

DOI: 10.1002/ijc.31532

Source: Alma/SFX Local Collection

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6

Article

Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study

Sun, Weili ; Malvar, Jemily ; Sposto, Richard ; [et al.]

2018

ISSN: 0887-6924

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Language: English

In: Leukemia, 2018-11, Vol.32 (11), p.2316-2325

Description: The survival of pediatric patients with multiply relapsed and/or refractory (R/R) B-cell acute lymphoblastic leukemia has historically been very poor; however, data are limited in the current era. We conducted a retrospective study to determine the outcome of multiply R/R childhood B-ALL treated at 24 TACL institutions between 2005 and 2013. Patient information, treatment, and response were collected. Prognostic factors influencing the complete remission (CR) rate and event-free survival (EFS) were analyzed. The analytic set included 578 salvage treatment attempts among 325 patients. CR rates (mean ± SE) were 51 ± 4% for patients with bone marrow R/R B-ALL who underwent a second salvage attempt, 37 ± 6% for a third attempt, and 31 ± 6% for the fourth through eighth attempts combined. For patients achieving a CR after their second, third, and fourth through eighth attempts, the 2 year EFS was 41 ± 6%, 13 ± 7%, and 27 ± 13% respectively. Our results showed slight improvement when compared to previous studies. This is the largest and most recent study to date that evaluates the outcome of this patient population. Our data will provide detailed reference for the evaluation of new agents being developed for childhood B-ALL.

ISSN: 0887-6924

E-ISSN: 1476-5551

DOI: 10.1038/s41375-018-0094-0

Source: Nature Open Access

Source: Alma/SFX Local Collection

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7

Article

High dose alkylator therapy for extracranial malignant rhabdoid tumors in children

Venkatramani, Rajkumar ; Shoureshi, Poone ; Malvar, Jemily ; [et al.]

2014

ISSN: 1545-5009

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Language: English

In: Pediatric blood & cancer, 2014-08, Vol.61 (8), p.1357-1361

Description: Background Extracranial malignant rhabdoid tumor (MRT) is a rare pediatric cancer with a poor prognosis. The kidney is the most common site. Isolated reports have shown improvements in patient survival, but no specific treatment regimen has shown efficacy over others. Procedure Retrospective review of patients diagnosed with extracranial MRT at Children's Hospital Los Angeles between 1983 and 2012. Results The median age at presentation for the 21 patients was 13 months (range, 0–108 months). Ten patients had renal primary tumors. The median time to progression was 4 months (range, 0.4–7 months). The 5‐year event free survival (EFS) and overall survival (OS) of the entire cohort was 38 ± 10.6%. After 2002, patients diagnosed with extracranial MRT were administered a chemotherapy regimen of vincristine, doxorubicin and high dose cyclophosphamide (VDC). The OS for the patients diagnosed before and after 2002 were 20 ± 12% and 54 ± 15%, respectively. Of the 13 patients who received VDC containing regimen, eight patients achieved a complete radiological remission; five of these patients are long‐term survivors. Four patients who received autologous bone marrow transplantation were alive at last follow‐up. All patients with unresectable primary tumors died. Patients who had disease progression or relapse did not survive. Conclusions Patients with extracranial MRT have a poor prognosis. Treatment with high dose alkylator therapy followed by consolidation with high dose chemotherapy and autologous bone marrow transplant for those patients in radiographic complete remission appears to have a beneficial effect on survival. Pediatr Blood Cancer 2014; 61:1357–1361. © 2014 Wiley Periodicals, Inc.

Subject(s): autologous bone marrow transplant ; radiation ; cyclophosphamide ; rhabdoid tumor ; chemotherapy ; extrarenal ; surgery ; Rhabdoid Tumor - drug therapy ; Humans ; Rhabdoid Tumor - mortality ; Child, Preschool ; Infant ; Survival Rate ; Antineoplastic Agents, Alkylating - administration & dosage ; Kidney Neoplasms - mortality ; Disease-Free Survival ; Female ; Retrospective Studies ; Kidney Neoplasms - drug therapy ; Child ; Infant, Newborn ; Care and treatment ; Chemotherapy ; Anthracyclines ; Cyclophosphamide ; Tumors ; Cancer ; Index Medicus

ISSN: 1545-5009

E-ISSN: 1545-5017

DOI: 10.1002/pbc.25093

Source: Alma/SFX Local Collection

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8

Article

Brain biomarkers and neuropsychological outcomes of pediatric posterior fossa brain tumor survivors treated with surgical resection with or without adjuvant chemotherapy

Baron Nelson, Mary C ; O'Neil, Sharon H ; Tanedo, Jeffrey ; [et al.]

2021

ISSN: 1545-5009

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Language: English

In: Pediatric blood & cancer, 2021-02, Vol.68 (2), p.e28817-n/a

Description: Purpose Children with brain tumors experience cognitive late effects, often related to cranial radiation. We sought to determine differential effects of surgery and chemotherapy on brain structure and neuropsychological outcomes in children who did not receive cranial radiation therapy (CRT). Methods Twenty‐eight children with a history of posterior fossa tumor (17 treated with surgery, 11 treated with surgery and chemotherapy) underwent neuroimaging and neuropsychological assessment a mean of 4.5 years (surgery group) to 9 years (surgery + chemotherapy group) posttreatment, along with 18 healthy sibling controls. Psychometric measures assessed IQ, language, executive functions, processing speed, memory, and social‐emotional functioning. Group differences and correlations between diffusion tensor imaging findings and psychometric scores were examined. Results The z‐score mapping demonstrated fractional anisotropy (FA) values were ≥2 standard deviations lower in white matter tracts, prefrontal cortex gray matter, hippocampus, thalamus, basal ganglia, and pons between patient groups, indicating microstructural damage associated with chemotherapy. Patients scored lower than controls on visuoconstructional reasoning and memory (P ≤ .02). Lower FA in the uncinate fasciculus (R = −0.82 to −0.91) and higher FA in the thalamus (R = 0.73‐0.91) associated with higher IQ scores, and higher FA in the thalamus associated with higher scores on spatial working memory (R = 0.82). Conclusions Posterior fossa brain tumor treatment with surgery and chemotherapy affects brain microstructure and neuropsychological functioning years into survivorship, with spatial processes the most vulnerable. Biomarkers indicating cellular changes in the thalamus, hippocampus, pons, prefrontal cortex, and white matter tracts associate with lower psychometric scores.

Subject(s): neuropsychology ; diffusion tensor imaging ; pediatric brain tumor ; survivors of childhood cancer ; neuroimaging ; Pediatrics ; Anisotropy ; Brain tumors ; Surgery ; Adjuvant treatment ; Radiation ; Biological markers ; Radiotherapy ; Cancer ; Index Medicus

ISSN: 1545-5009

E-ISSN: 1545-5017

DOI: 10.1002/pbc.28817

Source: Alma/SFX Local Collection

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9

Article

Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study

Oberley, Matthew J ; Raikar, Sunil S ; Wertheim, Gerald B ; [et al.]

2020

ISSN: 0887-6924

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Language: English

In: Leukemia, 2020-07, Vol.34 (7), p.1741-1750

Description: The rarity of mixed phenotype acute leukemia (MPAL) has precluded adequate data to incorporate minimal residual disease (MRD) monitoring into therapy. Fluidity in MPAL classification systems further complicates understanding its biology and outcomes; this includes uncertainty surrounding the impact of shifting diagnostic requirements even between iterations of the World Health Organization (WHO) classification. Our primary objective was to address these knowledge gaps. To do so, we analyzed clinicopathologic features, therapy, MRD, and survival in a centrally-reviewed, multicenter cohort of MPAL uniformly diagnosed by the WHO classification and treated with acute lymphoblastic leukemia (ALL) regimens. ALL induction therapy achieved an EOI MRD negative (〈0.01%) remission in most patients (70%). EOI MRD positivity was predictive of 5-year EFS (HR = 6.00, p 〈 0.001) and OS (HR = 9.57, p = 0.003). Patients who cleared MRD by EOC had worse survival compared with those EOI MRD negative. In contrast to adults with MPAL, ALL therapy without transplantation was adequate to treat most pediatric patients. Earlier MRD clearance was associated with better treatment success and survival. Prospective trials are now necessary to validate and refine MRD thresholds within the pediatric MPAL population and to identify salvage strategies for those with poor predicted survival.

Subject(s): Neoplasm, Residual - pathology ; United States - epidemiology ; Leukemia - pathology ; Prognosis ; Follow-Up Studies ; Humans ; Neoplasm, Residual - epidemiology ; Leukemia - therapy ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality ; Survival Rate ; Hematopoietic Stem Cell Transplantation - mortality ; Leukemia - classification ; Phenotype ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy ; Hematopoietic Stem Cell Transplantation - adverse effects ; Female ; Neoplasm, Residual - mortality ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Child ; Induction Chemotherapy - mortality ; Cohort Studies ; Leukemia - mortality ; Pediatrics ; Analysis ; Oncology, Experimental ; Acute leukemia ; Genetic aspects ; Children ; Research ; Health aspects ; Diseases ; Cancer ; Index Medicus

ISSN: 0887-6924

E-ISSN: 1476-5551

DOI: 10.1038/s41375-020-0741-0

Source: Nature Open Access

Source: Alma/SFX Local Collection

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10

Article

Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA‐mediated osteoblastogenesis

HaDuong, Josephine H ; Blavier, Laurence ; Baniwal, Sanjeev K ; [et al.]

2015

ISSN: 0020-7136

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Language: English

In: International journal of cancer, 2015-08-15, Vol.137 (4), p.797-809

Description: The potential role of osteoblasts in bone and bone marrow (BM) metastases in neuroblastoma (NBL) remains unclear. In this study, we examined the effect of NBL cells on the osteoblastic differentiation of BM‐derived mesenchymal stromal cells (BMMSC). We show that the presence of NBL cells enhanced the osteoblastic differentiation of BMMSC driven by bone morphogenetic protein (BMP)‐4, in the absence of any effect on NBL cell proliferation. Expression profiles of BMMSC driven toward osteoblastic differentiation revealed an increase in vascular endothelial growth factor A (Vegfa) expression in the presence of NBL cells. We demonstrated that NBL cells increased BMMSC‐derived VEGFA mRNA and protein and that this was enhanced by BMP‐4. However, in similar conditions, neither the addition of an mVEGFA blocking antibody nor exogenous recombinant (r) mVEGFA affected osteoblastic differentiation. In contrast, siRNA‐ mediated knock‐down of VEGFA in BMMSC prevented osteoblastic differentiation in BMP‐4‐treated cocultures, an effect that was not reversed in the presence of rmVEGFA. An analysis of murine bones injected with hNBL cells revealed an increase of mVEGFA producing cells near tumor cells concomitantly with an increase in Vegfa and Runx2 mRNA. This coincided with an increase in osteoclasts, in Rankl/Opg mRNA ratio and with the formation of osteolytic lesions. Thus NBL cells promote osteoblastogenesis in the BM by increasing VEGFA expression in BMMSC. Our study provides a new insight into the role of VEGFA in NBL metastases by pointing to the role of stroma‐derived intracrine VEGFA in osteoblastogenesis. What's new? Wandering cancer cells often find bone marrow a hospitable place to settle down and start a new tumor. The tumor cells accelerate bone cell turnover, which releases physiological factors that feed the tumor cell, promoting a vicious cycle. What mechanism drives this? This paper shows that neuroblastoma cells team up with the cytokine BMP‐4 to spur bone marrow mesenchymal cells to become osteoblasts. They also need to bump up production of VEGFA, suggesting that blocking VEGFA production could hinder bone metastasis.

Subject(s): neuroblastoma ; mesenchymal cells ; osteoblastogenesis ; VEGFA ; Cell Line ; Vascular Endothelial Growth Factor A - biosynthesis ; Cell Proliferation - genetics ; Humans ; Osteoprotegerin - biosynthesis ; Mesenchymal Stromal Cells - metabolism ; Vascular Endothelial Growth Factor A - genetics ; Cell Differentiation - genetics ; RNA, Messenger - biosynthesis ; Lymphocyte Activation - genetics ; Animals ; Core Binding Factor Alpha 1 Subunit - biosynthesis ; Gene Expression Regulation, Developmental ; Bone Morphogenetic Protein 4 - administration & dosage ; Mice ; Neuroblastoma - metabolism ; Osteoblasts - metabolism ; Bone morphogenetic proteins ; Neuroblastoma ; Endothelial growth factors ; RNA ; Analysis ; Stem cells ; Index Medicus ; Mesenchymal cells ; Osteoblastogenesis ; Vascular endothelial cell growth factor ; Metastasis

ISSN: 0020-7136

E-ISSN: 1097-0215

DOI: 10.1002/ijc.29465

Source: Alma/SFX Local Collection

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