Association of ALDH-expressing cancer stem cells with survival in patients with resected pancreatic adenocarcinoma treated with adjuvant chemoradiation.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 262-262
Author(s):  
Rachit Kumar ◽  
Avani Satish Dholakia ◽  
Joseph M. Herman ◽  
Anirban Maitra ◽  
William H. Matsui ◽  
...  
Keyword(s):  
Stem Cells ◽  
Overall Survival ◽  
Cancer Stem Cells ◽  
Pancreatic Adenocarcinoma ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Distant Metastases ◽  
Tumor Grade ◽  
Tumor Initiating Cells ◽  
Radiology Reports

262 Background: We and others have identified aldehyde dehydrogenase (ALDH) activity as a marker of pancreatic cancer stem cells (or tumor-initiating cells). The presence of cancer stem cells (CSCs) has been associated with decreased survival and treatment resistance in pancreatic adenocarcinoma. We investigate the role of ALDH expression in predicting survival and patterns of disease recurrence in patients treated with chemoradiation (CRT) following pancreatectomy. Methods: Tissue microarrays using surgical specimens from 1998 to 2002 were stained for ALDH1 and scored as ALDH-positive or ALDH-negative by two expert pancreatic pathologists blinded to patient outcomes. Physician documentation and radiology reports were used to determine follow-up information. Time to local failure (TLF), time to distant metastases (TDM), progression-free survival (PFS), and overall survival (OS) were analyzed using SPSS software. Results: Previously we found that ALDH expression was associated with worse OS in a cohort of 269 patients with resected pancreatic adenocarcinoma (Rasheed, JNCI 2009). From this cohort, adjuvant treatment information was available for 87 patients with ALDH-negative tumors (48.6%) and 41 patients with ALDH-positive tumors (45.6%). In patients treated with adjuvant CRT, median overall survival was superior in the ALDH-negative cohort vs. the ALDH-positive cohort, 26.3 months vs. 18.2 months (p=0.011). Further, in patients treated with adjuvant CRT, ALDH-negative patients had statistically greater TLF, TDM, and PFS than their ALDH-positive counterparts (see table). On multivariate analysis, ALDH positive tumor staining (HR 1.94, p=0.004) and tumor grade (HR 1.54, p=0.041) predicted lower OS, and ALDH positive tumor staining (HR 1.83, p=0.008), tumor grade (HR 1.52, p=0.038), and tumor size >3 cm (HR 1.65, p=0.023) predicted decreased PFS. Conclusions: This study suggests that adjuvant CRT improves TLF, TDM, PFS, and OS in patients with localized pancreatic adenocarcinoma not enriched with ALDH-expressing CSCs. Laboratory studies will help elucidate the mechanisms of treatment resistance in ALDH expressing CSCs.

scholarly journals Gemcitabine-Containing Chemotherapy for the Treatment of Metastatic Myxofibrosarcoma Refractory to Doxorubicin: A Case Series

2021 ◽  
Vol 28 (1) ◽  
pp. 813-817
Author(s):  
Arielle Elkrief ◽  
Suzanne Kazandjian ◽  
Thierry Alcindor
Keyword(s):  
Overall Survival ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Objective Response ◽  
Case Series ◽  
Progression Free Survival ◽  
Distant Metastases ◽  
First Line ◽  
Pleomorphic Sarcoma ◽  
Line Setting

Background: Myxofibrosarcoma is a type of soft-tissue sarcoma that is associated with high rates of local recurrence and distant metastases. The first-line treatment for metastatic soft-tissue sarcoma has conventionally been doxorubicin-based. Recent evidence suggests that myxofibrosarcoma may be molecularly similar to undifferentiated pleomorphic sarcoma (UPS), which is particularly sensitive to gemcitabine-based therapy. The goal of this study was to evaluate the activity of gemcitabine-containing regimens for the treatment of metastatic myxofibrosarcoma refractory to doxorubicin. Material and Methods: We retrospectively evaluated seven consecutive cases of metastatic myxofibrosarcoma at our institution treated with gemcitabine-based therapy in the second-line setting, after progression on doxorubicin. Baseline clinical and baseline characteristics were collected. Primary endpoints were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: After progression on first-line doxorubicin, a partial, or complete radiological response was observed in four of seven patients who received gemcitabine-based chemotherapy. With a median follow-up of 14 months, median progression-free and overall survival were 8.5 months and 11.4 months, respectively. Conclusions: Gemcitabine-based chemotherapy was associated with encouraging response rates in this cohort, similar to those seen in UPS. Both entities could be studied together for novel gemcitabine-based regimens.

scholarly journals The role of steroid hormones in breast cancer stem cells

2015 ◽  
Vol 22 (6) ◽  
pp. T177-T186 ◽  
Author(s):  
Bruno M Simões ◽  
Denis G Alferez ◽  
Sacha J Howell ◽  
Robert B Clarke
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Steroid Hormones ◽  
Normal Mammary Gland ◽  
Breast Cancer Stem Cells ◽  
Tumor Initiating Cells ◽  
Unit Of Selection ◽  
Selection For

Breast cancer stem cells (BCSCs) are potent tumor-initiating cells in breast cancer, the most common cancer among women. BCSCs have been suggested to play a key role in tumor initiation which can lead to disease progression and formation of metastases. Moreover, BCSCs are thought to be the unit of selection for therapy-resistant clones since they survive conventional treatments, such as chemotherapy, irradiation, and hormonal therapy. The importance of the role of hormones for both normal mammary gland and breast cancer development is well established, but it was not until recently that the effects of hormones on BCSCs have been investigated. This review will discuss recent studies highlighting how ovarian steroid hormones estrogen and progesterone, as well as therapies against them, can regulate BCSC activity.

scholarly journals Circulating Tumor Cells and Cancer Stem Cells: Clinical Implications in Nonmetastatic Breast Cancer

2016 ◽  
Vol 10 ◽  
pp. BCBCR.S40856 ◽  
Author(s):  
M. Sayed ◽  
A.M. Zahran ◽  
M.S.F. Hassan ◽  
D.O. Mohamed
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Overall Survival ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Disease Free Survival ◽  
Free Survival ◽  
The Third ◽  
Disease Free

Purpose Despite the therapeutic advances, disease recurrence remains an ever-present threat to the health and well-being of breast cancer survivors. Assessment of circulating tumor cells (CTCs) and cancer stem cells (CSCs) during and after treatment may be of value in refining treatment. Methods Three 5 mL blood samples were taken from each patient: the first, at diagnosis; the second, after completion of neoadjuvant anthracyclin-based chemotherapy; and the third, a month after surgery and completion of adjuvant radiotherapy. The absolute numbers of CTCs were identified as CD45-cytokeratin+ cells. CTCs per 5 mL of blood were determined by recording all events in the whole suspension. CSCs were identified as cytokeratin+CD44+CD24-/CD45- cells. The CSCs were expressed as a percentage of CTCs. Results Univariate analysis identified the measurements of baseline CTCs and CSCs, taken after chemotherapy and one month after the cessation of radiotherapy, as prognostic factors for both four-year disease-free survival and four-year overall survival. Multivariable analysis identified the third measurement of CSCs, taken one month after the completion of radiotherapy, as the only independent prognostic factor for the four-year disease-free survival (P < 0.002, hazard ratio [HR] = 1.231, 95% CI 1.077–1.407). The initial CTC measurement was the one factor that reached significance on multivariate analysis (P < 0.03, HR 1.969, 95% CI 1.092–3.551) for the four-year overall survival. Correlation was higher between CTC and CSC counts at diagnosis ( r = 0.654, P < 0.001) than after chemotherapy ( r = 0.317, P < 0.03), because of the more rapid decrease in the mean CTC count with chemotherapy. Conclusion The CTC count could be suitable as one of the measures for monitoring response to chemotherapy, while persistence of CSC after cessation of the treatment of nonmetastatic breast cancer, except hormonal therapy when indicated, may be a reason to consider additional therapy in the future. These findings need confirmation in larger randomized trials.

scholarly journals Cancer stem cells markers associated with development and aggressive phenotype in pancreatic cancer

2020 ◽  
pp. 102-122
Author(s):  
Camila Juliano Salvador Rodrigues ◽  
Elita Ferreira da Silveira ◽  
Rafael da Silveira Vargas ◽  
Giordano Gatti de Giacomo ◽  
Marino Muxfeldt Bianchin
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Development ◽  
Staining Intensity ◽  
Ductal Adenocarcinoma ◽  
Clinicopathological Parameters ◽  
Tumor Initiating Cells ◽  
New Ideas

Background: Cancer stem cells, also known as tumor-initiating cells, are suggested to be responsible for drug resistance and cancer development due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells. Objective: This study was designed to investigate the role of cancer stem cells in pancreatic cancer. Methods: A retrospective clinicopathological analysis was undertaken in 112 patients diagnosed with pancreatic ductal adenocarcinoma between 2005 and 2010, and immunohistochemistry was performed with antibodies against CD133, CD24, and OCT4. Positive nuclear, cytoplasmic or membrane staining for each antibody was rated on staining intensity, being classified into low/moderate or strong staining groups. Results were analyzed relative to each patient’s clinicopathological parameters. Results: There was an established relationship between the staining of the markers with some variables associated with worse prognosis, being the three markers present in most tumor cells and associated with tumor progression. We suppose that cancer stem cells are present from the beginning of tumor initiation and are intrinsically related to tumor development. Although the presence of stem cells has been associated with molecular biology of various tumors, their expression in pancreatic cancer has not yet been clinically reported. Conclusion: The presence of stem cells and their role in pancreatic cancer tumorigenesis may be considered as valuable prognostic factors, although the mechanism involved needs further investigation. Increasing insights into role of cancer stem cells and carcinogenesis can ultimately generate new ideas for molecularly based diagnostic and therapeutic approaches.

Cancer stem cells

2019 ◽  
pp. 283-300
Author(s):  
Connor Sweeney ◽  
Lynn Quek ◽  
Betty Gration ◽  
Paresh Vyas
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Experimental Studies ◽  
Treatment Resistance ◽  
Experimental Models ◽  
Self Renewal ◽  
Multipotent Stem Cells ◽  
Anticancer Chemotherapy ◽  
Normal Tissues ◽  
Oncogenic Mutation

The concept of cancer stem cells (CSCs) emerged from our understanding of the way in which normal tissues are generated from multipotent stem cells. Regenerative tissues exhibit a cellular hierarchy of differentiation, which is maintained by stem cells. Evidence from experimental models has indicated that a similar hierarchy is seen in at least some cancers, where CSCs give rise to disordered and dysfunctional tissues, leading to disease. The CSC model proposes that tumours can be divided into at least two distinct populations. The stem cells are a specialized population of cancer cells with the unique property of long-term self-renewal that maintain the growth of the cancerous clone. These stem cells give rise to the second population of cells, which form the bulk of the tumour, and lack indefinite self-renewal. Recently, our understanding of CSCs has been refined through combining genetic, epigenetic, and functional models of tumorigenesis. Malignant transformation occurs as the result of sequential acquisition of genetic mutations. Capacity for self-renewal is essential for a clone to survive and progress to become cancerous. If an oncogenic mutation occurs in a cell that is incapable of self-renewal, the clone will become exhausted through differentiation. CSCs may survive anticancer chemotherapy and increasing evidence indicates their role in mediating treatment resistance and relapse. Therefore, strategies to eradicate cancers must effectively target the stem cells that maintain their growth. CSC-directed therapeutic strategies are currently being explored in experimental studies and clinical trials but reducing toxicity to normal tissue stem cells represents a significant challenge.

scholarly journals Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1058 ◽  
Author(s):  
Gener ◽  
Rafael ◽  
Seras-Franzoso ◽  
Perez ◽  
Pindado ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Distant Metastases ◽  
Metastatic Potential ◽  
Phenotypic Change ◽  
Primary Tumors ◽  
Mesenchymal Transition

Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.

scholarly journals Is there an oligometastatic state in pancreatic cancer? Practical clinical considerations raise the question

2020 ◽  
Vol 93 (1106) ◽  
pp. 20190627
Author(s):  
Marta Scorsetti ◽  
Tiziana Comito ◽  
Davide Franceschini ◽  
Ciro Franzese ◽  
Maria Giuseppina Prete ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Pancreatic Adenocarcinoma ◽  
Local Treatment ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Free Survival ◽  
Number Of Patients ◽  
Clinical Considerations

Objectives: To evaluate the role of stereotactic body radiotherapy (SBRT) as a local ablative treatment (LAT) in oligometastatic pancreatic cancer. Methods: Patients affected by histologically confirmed stage IV pancreatic adenocarcinoma were included in this analysis. Endpoints are local control (LC), progression-free survival (PFS), and overall survival (OS). Results: From 2013 to 2017, a total of 41 patients were treated with SBRT on 64 metastases. Most common sites of disease were lung (29.3%) and liver (56.1%). LC at 1 and 2 years were 88.9% (95% CI 73.2–98.6) and 73.9% (95% CI 50–87.5), respectively. Median LC was 39.9 months (95% CI 23.3—not reached). PFS rates at 1 and 2 years were 21.9% (95% CI 10.8–35.4) and 10.9% (95% CI 3.4–23.4), respectively. Median PFS was 5.4 months (95%CI 3.1–11.3). OS rates at 1 and 2 years were 79.9% (95% CI 63.7–89.4) and 46.7% (95% CI 29.6–62.2). Median OS was 23 months (95%CI 14.1–31.8). Conclusions: Our results, although based on a retrospective analysis of a small number of patients, show that patients with oligometastatic pancreatic cancer may benefit from local treatment with SBRT. Larger studies are warranted to confirm these results. Advances in knowledge: Selected patients affected by oligometastatic pancreatic adenocarcinoma can benefit from local ablative approaches, like SBRT

P3.68. Cancer stem cells as mediators of treatment resistance in squamous cell carcinoma of the head and neck

2009 ◽  
Vol 3 (1) ◽  
pp. 224
Author(s):  
A. Okamoto ◽  
K. Chikamatsu ◽  
K. Sakakura ◽  
K. Hatsushika ◽  
G. Takahashi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Squamous Cell Carcinoma ◽  
Cancer Stem Cells ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Treatment Resistance

Next-generation nanotheranostics targeting cancer stem cells

Nanomedicine ◽  
2019 ◽  
Vol 14 (18) ◽  
pp. 2487-2514 ◽  
Author(s):  
Asmaa Reda ◽  
Salma Hosseiny ◽  
Ibrahim M El-Sherbiny
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Causes Of Death ◽  
Treatment Strategies ◽  
Next Generation ◽  
Tumor Initiating Cells ◽  
Dna Repair Mechanisms ◽  
Proliferation And Differentiation ◽  
Repair Mechanisms ◽  
Opening Up

Cancer is depicted as the most aggressive malignancy and is one the major causes of death worldwide. It originates from immortal tumor-initiating cells called ‘cancer stem cells’ (CSCs). This devastating subpopulation exhibit potent self-renewal, proliferation and differentiation characteristics. Dynamic DNA repair mechanisms can sustain the immortality phenotype of cancer to evade all treatment strategies. To date, current conventional chemo- and radio-therapeutic strategies adopted against cancer fail in tackling CSCs. However, new advances in nanotechnology have paved the way for creating next-generation nanotheranostics as multifunctional smart ‘all-in-one’ nanoparticles. These particles integrate diagnostic, therapeutic and targeting agents into one single biocompatible and biodegradable carrier, opening up new avenues for breakthroughs in early detection, diagnosis and treatment of cancer through efficient targeting of CSCs.

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