Autonomous growth of blast cells is associated with reduced survival in acute myeloblastic leukemia

We have previously classified the in vitro growth characteristics of clonogenic blasts from patients with acute myeloblastic leukemia (AML) according to their capacity to proliferate autonomously in a blast cell colony assay. Here we have analyzed whether the presence of in vitro autonomous growth characteristics has any clinical relevance in AML. We have studied 50 patients (age 2 to 64 years), all of whom were treated with combination chemotherapy, excluding patients with a history of antecedent myelodysplasia. Leukemic cells from 34 of 50 patients (68%) exhibited either partial or totally autonomous growth in a blast cell colony assay. Cells from the remaining patients exhibited nonautonomous growth and were either totally dependent on exogenous growth factor (n = 8) or failed to proliferate at all in the culture system used (n = 8). All 50 patients were treated by intensive chemotherapy and 69% achieved complete remission (CR). Patients whose blasts exhibited autonomous growth in vitro had a significantly lower CR rate (57%) compared with the 16 patients with nonautonomous growth (94%, P = .02). White blood cell count was the only other significant factor (P = .03), but in multivariate analysis growth characteristics remains the most important predictor of CR. Actuarial relapse risk is 80% and 42% at 5 years for autonomous and nonautonomous groups respectively (P = .1). Overall disease-free survival is 21.8% and is higher in the nonautonomous growth group at 54.2% compared with 11.3% at 5 years (P = .0015) in the autonomous growth characteristics was found to be the single most important indicator of CR and disease-free survival. Our data suggests that the suppression of autocrine growth factor production may be of value in the treatment of AML.

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Autonomous growth of blast cells is associated with reduced survival in acute myeloblastic leukemia

Blood ◽

10.1182/blood.v82.3.899.899 ◽

1993 ◽

Vol 82 (3) ◽

pp. 899-903 ◽

Cited By ~ 54

Author(s):

AE Hunter ◽

SY Rogers ◽

IA Roberts ◽

AJ Barrett ◽

N Russell

Keyword(s):

Growth Factor ◽

Disease Free Survival ◽

Blast Cell ◽

Growth Characteristics ◽

Free Survival ◽

Colony Assay ◽

Disease Free ◽

Cell Colony ◽

Autonomous Growth

Abstract We have previously classified the in vitro growth characteristics of clonogenic blasts from patients with acute myeloblastic leukemia (AML) according to their capacity to proliferate autonomously in a blast cell colony assay. Here we have analyzed whether the presence of in vitro autonomous growth characteristics has any clinical relevance in AML. We have studied 50 patients (age 2 to 64 years), all of whom were treated with combination chemotherapy, excluding patients with a history of antecedent myelodysplasia. Leukemic cells from 34 of 50 patients (68%) exhibited either partial or totally autonomous growth in a blast cell colony assay. Cells from the remaining patients exhibited nonautonomous growth and were either totally dependent on exogenous growth factor (n = 8) or failed to proliferate at all in the culture system used (n = 8). All 50 patients were treated by intensive chemotherapy and 69% achieved complete remission (CR). Patients whose blasts exhibited autonomous growth in vitro had a significantly lower CR rate (57%) compared with the 16 patients with nonautonomous growth (94%, P = .02). White blood cell count was the only other significant factor (P = .03), but in multivariate analysis growth characteristics remains the most important predictor of CR. Actuarial relapse risk is 80% and 42% at 5 years for autonomous and nonautonomous groups respectively (P = .1). Overall disease-free survival is 21.8% and is higher in the nonautonomous growth group at 54.2% compared with 11.3% at 5 years (P = .0015) in the autonomous growth characteristics was found to be the single most important indicator of CR and disease-free survival. Our data suggests that the suppression of autocrine growth factor production may be of value in the treatment of AML.

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TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

Cell Death and Disease ◽

10.1038/s41419-021-03734-4 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Sha Zhou ◽

Jianhong Peng ◽

Liuniu Xiao ◽

Caixia Zhou ◽

Yujing Fang ◽

...

Keyword(s):

Colorectal Cancer ◽

Disease Free Survival ◽

Free Survival ◽

Epigenetic Regulator ◽

Crc Management ◽

Disease Free ◽

Resistance To Chemotherapy

AbstractResistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.

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Prognostic role of c-met tyrosine kinase receptor expression in breast carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10552 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10552-10552

Author(s):

I. Gisterek ◽

R. Matkowski ◽

E. Suder ◽

A. Lacko ◽

D. Ramsey ◽

...

Keyword(s):

Growth Factor ◽

Breast Carcinoma ◽

Biological Effects ◽

Statistical Significance ◽

Disease Free Survival ◽

Receptor Expression ◽

Tyrosine Kinase Receptor ◽

Immunoperoxidase Technique ◽

Free Survival ◽

Disease Free

10552 Background: Hepatocyte growth factor is a pleotropic growth factor that regulates cell proliferation, survival, tumor angiogenesis and metastasis. Its biological effects are mediated through interaction with its receptor: c-met protein.In this study, we evaluated c-met expression in the homogenous group of 99 patients diagnosed with stage II ductal breast carcinomas (G2, G3). We analyzed 5 and 10-years overall (OS) and disease free survival (DFS). Methods: Microscopic studies were performed on formalin-fixed, paraffin-embedded tumor tissue, obtained during surgery and stained routinely with haematoxylin and eosin. Expression of c-met was evaluated using a standard immunoperoxidase technique and percentage of cells with protein expression was counted. Survival was estimated using Kaplan-Meier method. Results: The expression of c-met was found in 37 (37.37%) tumors, with the strong expression of c-met observed only in 7 (7.07%) specimens. The 5-year DFS in patients with overexpression of c-met was statistically significantly worse (p =0.00493) compared with the group with low or no expression (recurrent rates: 57.14% vs 20.65%). Also with a time horizon of 10 years, high values of c-met expression were associated with the higher rate of recurrences (71.43% vs 30.77%, p = 0.01351). The 5-years OS rate in patients with c-met overexpression was 71.43% compared with 84.78% in the group with low or no expression, but this result did not reach statistical significance (p = 0.30345). Comparable tendency was seen in 10-years OS, which was 42.86% in patients with overexpression and 73.63% with low or no expression (p = 0.06154). Conclusions: The results of the study suggest that c-met overexpression is associated with shorter disease-free survival and it may be a useful prognostic indicator of more aggressive disease in patients with breast carcinoma. No significant financial relationships to disclose.

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Different effects of insulin-like growth factor-1 receptor expression on prognosis of estrogen receptor positive versus triple-negative invasive ductal breast carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.3546 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 3546-3546

Author(s):

J. Wesseling ◽

H. Hartog ◽

H. Horlings ◽

B. van der Vegt ◽

A. Ajouaou ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

Growth Factor ◽

Triple Negative ◽

Systemic Treatment ◽

Disease Free Survival ◽

P Value ◽

Invasive Ductal Breast Carcinoma ◽

Free Survival ◽

Disease Free

3546 Background: The insulin-like growth factor type 1 receptor (IGF-1R) is involved in progression and sensitivity to systemic treatment of breast cancer. Moreover, targeted inhibition of IGF-1R is likely to be beneficial in systemic treatment. However, it is unknown how to select patients for IGF-1R targeted therapy. Therefore, we studied the relation between IGF-1R expression and prognosis in invasive ductal breast carcinomas. Methods: Immunohistochemistry was performed on tumor tissue of a consecutive cohort of 429 female patients treated for operable primary invasive ductal breast carcinoma. TMA sections were stained with antibodies against IGF1-R, insulin receptor (IR), ER, PR, HER-2, epidermal growth factor receptor (EGFR) and phosphorylated-Akt (p-Akt). Cytoplasmic and membranous IGF-1R staining were scored separately, as the relevance of IGF-1R cellular localization is yet unknown. Associations between IGF-1R expression with clinical and tumor characteristics were evaluated in a multivariate Cox regression model. To study in more detail the prognostic role of IGF-1R expression in triple negative invasive ductal carcinomas (TN IDCs), 51 TN IDCs from the series described above were combined with 64 TN IDCs from an independent dataset with similar patient and clinico-pathological characteristics. Results: Patients with tumors expressing both ER and cytoplasmic IGF-1R have a longer disease free survival (HR = 0.20; 95% CI 0.07 - 0.63; p-value = 0.006) and breast cancer specific survival (HR = 0.20, 95% CI 0.07 - 0.63, p-value = 0.002), independent of other known prognostic factors. Conversely, in the combined series of 105 TN IDCs, cytoplasmic IGF-1R expression was associated with a shorter disease free survival (HR = 2.29; 95% CI 1.08 - 4.48, p-value = 0.03). In a multivariate model including known prognostic factors, cytoplasmic IGF-1R expression was nearly significantly related to a shorter disease free survival (HR 2.06; 95% CI 0.95 - 4.47; p = 0.07). Conclusions: The favorable versus unfavorable association with prognosis of IGF-1R expression in ER positive versus TN IDCs may provide new opportunities to select patients for IGF-1R targeted therapy. No significant financial relationships to disclose.

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STIL-a novel link in Shh and Wnt signaling, endowing oncogenic and stem like attributes to colorectal cancer

10.1101/2020.07.30.226654 ◽

2020 ◽

Author(s):

Tapas Pradhan ◽

Vikas Kumar ◽

H Evangeline Surya ◽

R Krishna ◽

Samu John ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Importance ◽

Disease Free Survival ◽

Drug Resistant ◽

Free Survival ◽

Over Expression ◽

Disease Free

AbstractDiscovery of potent gene regulating tumorigenesis and drug resistance is of high clinical importance. STIL is an oncogene, however its molecular insights and role in colorectal oncogenesis are unknown. In this study we have explored role of STIL in tumorigenesis and studied its molecular targets in colorectal cancer (CRC). STIL silencing reduced proliferation and tumor growth in CRC. Further, STIL was found to regulate stemness markers CD133 & CD44 and drug resistant markers Thymidylate synthase, ABCB1 & ABCG2 both in in-vitro and in-vivo CRC models. In addition, over expression of STIL mRNA was found to be associated with reduced disease free survival in CRC cases. To our surprise we observed an Shh independent regulation of stemness and drug resistant genes mediated by STIL. Interestingly, we found an Shh independent regulation of β-catenin mediated by STIL via p-AKT, which partially answers Shh independent regulatory mechanism of CSC markers by STIL. Our study suggest an instrumental role of STIL in molecular manifestation of CRC and progression.

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The role of vascular endothelial growth factor as a prognostic and clinicopathological marker in osteosarcoma: a systematic review and meta-analysis

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-021-02888-3 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Chao Zhang ◽

Lin Wang ◽

Chuang Xiong ◽

Runhan Zhao ◽

Hao Liang ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Overall Survival ◽

Growth Factor ◽

Meta Analysis ◽

Disease Free Survival ◽

Vascular Endothelial ◽

Vegf Expression ◽

Free Survival ◽

Endothelial Growth Factor ◽

Disease Free

Abstract Background In recent years, numerous investigations have been conducted to determine the clinical significance and critical functions of vascular endothelial growth factor (VEGF) in various malignant cancers. The purpose of this meta-analysis was to comprehensively evaluate the prognostic and clinicopathological value of VEGF in patients with osteosarcoma. Methods We performed a systematic literature retrieval of available databases. Odds ratios (ORs) or standard mean difference (SMD) for clinicopathological parameters, hazard ratios (HRs) for overall survival and disease-free survival were calculated to assess the correlation between VEGF expression and prognosis in patients with osteosarcoma. Results A total of 22 studies with 1144 patients were included in our study. Pooled analyses showed that VEGF overexpression predicted worse overall survival (HR, 2.42; 95% CI, 1.87–3.11, p < 0.001) and disease-free survival (HR, 2.604; 95% CI, 1.698–3.995, p < 0.001), respectively. Furthermore, investigation regarding osteosarcoma clinicopathologic characteristics suggested that high VEGF expression was significantly associated with metastasis (OR, 4.39; 95% CI, 2.77–6.95; p < 0.001), clinical stage (OR, 0.73; 95% CI, 0.62–0.87; p < 0.001), and microvessel density (SMD, 3.33, 95% CI,1.57–5.10, p < 0.001), but not associated with tumor location, gender, age, local recurrence, and chemotherapy response. Conclusion Our meta-analysis findings suggest that elevated VEGF expression may be a predictive biomarker for poor prognosis and adverse clinicopathological characteristics in patients with osteosarcoma.

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Insulin-like Growth Factor 2 Expression Modulates Taxol Resistance and Is a Candidate Biomarker for Reduced Disease-Free Survival in Ovarian Cancer

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-09-3233 ◽

2010 ◽

Vol 16 (11) ◽

pp. 2999-3010 ◽

Cited By ~ 60

Author(s):

Gloria S. Huang ◽

Jurriaan Brouwer-Visser ◽

Marissa J. Ramirez ◽

Christine H. Kim ◽

Tiffany M. Hebert ◽

...

Keyword(s):

Ovarian Cancer ◽

Growth Factor ◽

Disease Free Survival ◽

Insulin Like Growth Factor ◽

Free Survival ◽

Taxol Resistance ◽

Disease Free

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Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma

Endocrine Related Cancer ◽

10.1677/erc-09-0153 ◽

2010 ◽

Vol 17 (1) ◽

pp. 191-202 ◽

Cited By ~ 43

Author(s):

Shahab Uddin ◽

Prashant Bavi ◽

Abdul K Siraj ◽

Maqbool Ahmed ◽

Maha Al-Rasheed ◽

...

Keyword(s):

Signaling Pathway ◽

Prognostic Marker ◽

Disease Free Survival ◽

Akt Signaling ◽

Papillary Thyroid ◽

Akt Signaling Pathway ◽

Free Survival ◽

Disease Free

The putative role of leptin and its receptor (Ob-R) in the pathogenesis of various primary human malignancies has been reported; however, their role in papillary thyroid cancer (PTC) has not yet been evaluated. We investigated the role of Ob-R in a large tissue microarray cohort of PTC followed by in vitro studies using a panel of PTC cell lines. Ob-R overexpression was seen in 80% PTCs and was significantly associated with poor disease-free survival (P=0.0235). PTCs that overexpressed Ob-R showed a aggressive phenotype characterized by older age, extrathyroid extension, larger tumor size, nodal metastasis, advanced stage, tall cell variant histological subtype, and a poor disease-free survival (P=0.0005, P=0.0006, P=0.0398, P=0.0004, P=0.0111, P=0.0003, and P=0.0235 respectively). However, Ob-R expression was not an independent prognostic marker to predict disease-free survival in multivariate analysis. PTCs with overexpression of Ob-R showed a significant direct association with overexpression of XIAP (P<0.0001) and Bcl-XL (P<0.0001). In vitro analysis showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of phosphatidylinisitol 3′ kinase (PI3K)/protein kinase B (AKT) signaling pathway. Inhibition of PI3K activity by its inhibitor LY294002 abrogated leptin-mediated PI3K/AKT signaling. Gene silencing of Ob-R in PTC cells resulted in downregulation of phospho-AKT, Bcl-XL, and XIAP expression suggesting that leptin-mediated pathogenesis of PTC occurs via involvement of these downstream targets. Altogether, these data show that leptin plays an important role in PTC pathogenesis through PI3K/AKT pathway via Ob-R and is a potential prognostic marker associated with an aggressive phenotype and poor disease-free survival.

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