scholarly journals Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells

2016 ◽  
Vol 213 (13) ◽  
pp. 2967-2988 ◽  
Author(s):  
Tze-Sian Chan ◽  
Chung-Chi Hsu ◽  
Vincent C. Pai ◽  
Wen-Ying Liao ◽  
Shenq-Shyang Huang ◽  
...  
Keyword(s):  
Treatment Resistance ◽  
Metronomic Chemotherapy ◽  
Tumor Stroma ◽  
Maximum Tolerated Dose ◽  
Carcinoma Cells ◽  
Paracrine Signaling ◽  
Tumor Initiating Cells ◽  
Growth And Survival ◽  
Impact On Treatment ◽  
Carcinoma Associated Fibroblasts

Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy–treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif–positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR+ chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy.

scholarly journals Therapy-activated stromal cells can dictate tumor fate

2016 ◽  
Vol 213 (13) ◽  
pp. 2831-2833 ◽  
Author(s):  
Robert S. Kerbel ◽  
Yuval Shaked
Keyword(s):  
Tumor Growth ◽  
Stromal Cells ◽  
Chemokine Receptors ◽  
Low Dose ◽  
Metronomic Chemotherapy ◽  
Tumor Stroma ◽  
Invasion And Metastasis ◽  
Inhibit Tumor Growth ◽  
Tumor Initiating Cells ◽  
Therapeutic Implications

In this issue of JEM, Chan et al. describe a novel way by which an investigational form of chemotherapy known as low-dose metronomic chemotherapy can inhibit tumor growth, which also has therapeutic implications for targeting tumor-initiating cells (TICs), the tumor stroma, and chemokine receptors, as well as invasion and metastasis.

scholarly journals The Blockade of Tumoral IL1β-Mediated Signaling in Normal Colonic Fibroblasts Sensitizes Tumor Cells to Chemotherapy and Prevents Inflammatory CAF Activation

2021 ◽  
Vol 22 (9) ◽  
pp. 4960
Author(s):  
Natalia Guillén Díaz-Maroto ◽  
Gemma Garcia-Vicién ◽  
Giovanna Polcaro ◽  
María Bañuls ◽  
Nerea Albert ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Colorectal Tumor ◽  
Cytotoxic Drugs ◽  
Differential Sensitivity ◽  
Paracrine Signaling ◽  
Inflammatory Phenotype ◽  
Heterotypic Interactions ◽  
Carcinoma Associated Fibroblasts

Heterotypic interactions between newly transformed cells and normal surrounding cells define tumor’s fate in incipient carcinomas. Once homeostasis has been lost, normal resident fibroblasts become carcinoma-associated fibroblasts, conferring protumorogenic properties on these normal cells. Here we describe the IL1β-mediated interplay between cancer cells and normal colonic myofibroblasts (NCFs), which bestows differential sensitivity to cytotoxic drugs on tumor cells. We used NCFs, their conditioned media (CM), and cocultures with tumor cells to characterize the IL1β-mediated crosstalk between both cell types. We silenced IL1β in tumor cells to demonstrate that such cells do not exert an influence on NCFs inflammatory phenotype. Our results shows that IL1β is overexpressed in cocultured tumor cells. IL1β enables paracrine signaling in myofibroblasts, converting them into inflammatory-CAFs (iCAF). IL1β-stimulated-NCF-CM induces migration and differential sensitivity to oxaliplatin in colorectal tumor cells. Such chemoprotective effect has not been evidenced for TGFβ1-driven NCFs. IL1β induces the loss of a myofibroblastic phenotype in NCFs and acquisition of iCAF traits. In conclusion, IL1β-secreted by cancer cells modify surrounding normal fibroblasts to confer protumorogenic features on them, particularly tolerance to cytotoxic drugs. The use of IL1β-blocking agents might help to avoid the iCAF traits acquisition and consequently to counteract the protumorogenic actions these cells.

scholarly journals Dynamic Stromal Alterations Influence Tumor-Stroma Crosstalk to Promote Pancreatic Cancer and Treatment Resistance

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3481
Author(s):  
Kendelle J. Murphy ◽  
Cecilia R. Chambers ◽  
David Herrmann ◽  
Paul Timpson ◽  
Brooke A. Pereira
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Development ◽  
Treatment Resistance ◽  
Tumor Stroma ◽  
Response To Treatment ◽  
Ductal Adenocarcinoma ◽  
Cell Phenotype ◽  
Stromal Compartment ◽  
Clinical Prognosis ◽  
Functional Value

Many cancer studies now recognize that disease initiation, progression, and response to treatment are strongly influenced by the microenvironmental niche. Widespread desmoplasia, or fibrosis, is fundamental to pancreatic cancer development, growth, metastasis, and treatment resistance. This fibrotic landscape is largely regulated by cancer-associated fibroblasts (CAFs), which deposit and remodel extracellular matrix (ECM) in the tumor microenvironment (TME). This review will explore the prognostic and functional value of the stromal compartment in predicting outcomes and clinical prognosis in pancreatic ductal adenocarcinoma (PDAC). We will also discuss the major dynamic stromal alterations that occur in the pancreatic TME during tumor development and progression, and how the stromal ECM can influence cancer cell phenotype, metabolism, and immune response from a biochemical and biomechanical viewpoint. Lastly, we will provide an outlook on the latest clinical advances in the field of anti-fibrotic co-targeting in combination with chemotherapy or immunotherapy in PDAC, providing insight into the current challenges in treating this highly aggressive, fibrotic malignancy.

scholarly journals Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

2019 ◽  
Vol 2019 ◽  
pp. 1-31 ◽  
Author(s):  
Cem Simsek ◽  
Ece Esin ◽  
Suayib Yalcin
Keyword(s):  
Clinical Studies ◽  
Lower Cost ◽  
Metronomic Chemotherapy ◽  
Maximum Tolerated Dose ◽  
Cancer Management ◽  
The Past ◽  
Promising Therapeutic Approach ◽  
Treatment Models ◽  
Dose Dense ◽  
Preclinical And Clinical Studies

Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts’ immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.

scholarly journals Anti-Angiogenic Effect of Orally Available Pemetrexed for Metronomic Chemotherapy

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 332 ◽  
Author(s):  
Maharjan ◽  
Pangeni ◽  
Jha ◽  
Choi ◽  
Chang ◽  
...  
Keyword(s):  
Cell Monolayer ◽  
Angiogenesis Inhibitor ◽  
Xenograft Model ◽  
Metronomic Chemotherapy ◽  
Fold Increase ◽  
Oral Formulation ◽  
Treated Group ◽  
Maximum Tolerated Dose ◽  
Oral Route ◽  
Angiogenic Effect

Metronomic chemotherapy (MCT) is defined as the frequent administration of low-dose chemotherapeutics, without long drug-free periods, with the exertion of antitumor activity exclusively through anti-angiogenic mechanisms. In this study, we have developed an orally available formulation of pemetrexed (PMX) for MCT. PMX was first complexed ionically with Nα-deoxycholyl-l-lysyl-methylester (DCK) as the permeation enhancer. This was followed by dispersion with poloxamer 188 and Labrasol to form the solid oral formulation of PMX (PMX/DCK-OP). PMX/DCK-OP exhibited a 10.6-fold increase in permeability across a Caco-2 cell monolayer compared to PMX alone. This resulted in a 70-fold increase in the oral bioavailability of PMX/DCK-OP in mice over oral PMX alone. In the A549 xenograft model, tumor volume was reduced by 51.1% in the PMX/DCK-OP treated group compared to only 32.8% in the maximum tolerated dose (MTD)-treated group. Furthermore, PMX/DCK-OP exhibited a significant anti-angiogenic effect on the A549 xenograft mice when compared to the MTD-treated group, as indicated by microvessel density quantification for CD-31. In addition, PMX/DCK-OP enhanced the release of an endogenous angiogenesis inhibitor, thrombospondin-1 (TSP-1), into both the blood circulation and the tumor microenvironment. Therefore, due to its oral route of administration, PMX/DCK-OP appears to be a better alternative to the conventional treatment of PMX.

Metastatic feline mammary cancer: prognostic factors, outcome and comparison of different treatment modalities – a retrospective multicentre study

2020 ◽  
pp. 1098612X2096441
Author(s):  
Gonçalo Petrucci ◽  
Joaquim Henriques ◽  
Hugo Gregório ◽  
Gonçalo Vicente ◽  
Justina Prada ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Adjuvant Treatment ◽  
Imaging Techniques ◽  
Treatment Options ◽  
Clinical Signs ◽  
Stage Iv ◽  
Metronomic Chemotherapy ◽  
Maximum Tolerated Dose ◽  
Treatment Modalities ◽  
Number Of Patients

Objectives Although feline mammary carcinomas (FMCs) are highly metastatic, the literature and treatment options pertaining to advanced tumours are scarce. This study aimed to investigate the clinical outcome of metastatic FMC with or without adjuvant treatment. Methods The medical records of 73 cats with metastatic FMC (stage 4) were reviewed and included in this study. Metastatic disease was detected by distinct imaging techniques (radiography, ultrasound and CT) and confirmed by cytology and/or histopathology. Cats with adjuvant chemotherapy treatment (n = 34) were divided into three groups: group 1 (n = 9) cats receiving maximum tolerated dose chemotherapy; group 2 (n = 15) cats receiving metronomic chemotherapy; and group 3 (n = 10) cats treated with toceranib phosphate. The study endpoints were time to progression (TTP) and tumour-specific survival (TSS). Treatment-related toxicity was evaluated according to the Veterinary Co-operative Oncology Group’s Common Terminology Criteria for Adverse Events version 1.1 (VCOG-CTCAE). Results Overall mean TTP and TSS were 23 and 44 days, respectively. Cats with clinical signs at the time of diagnosis had a lower TSS (14 days) than asymptomatic cats (120 days; P <0.001). Cats with pleural effusion had a lower TSS (16 days) than cats without ( P <0.001). Median TSS was 58, 75 and 63 in groups 1, 2 and 3, respectively ( P = 0.197). Toxicity was observed in 66.7%, 20% and 30% of cats in groups 1, 2 and 3, respectively. Conclusions and relevance To the best of our knowledge, this study includes the highest number of patients with metastatic FMC assessed. Despite the overall poor prognosis, some cats survived >6 months, indicating that adjuvant treatment may be an option to consider in metastatic disease. More studies are warranted for better understanding and management of stage IV patients.

scholarly journals Next Viable Routes to Targeting Pancreatic Cancer Stemness: Learning from Clinical Setbacks

2019 ◽  
Vol 8 (5) ◽  
pp. 702 ◽  
Author(s):  
Kelvin K. Tsai ◽  
Tze-Sian Chan ◽  
Yuval Shaked
Keyword(s):  
Clinical Trial ◽  
Treatment Resistance ◽  
Metronomic Chemotherapy ◽  
Therapeutic Strategies ◽  
Ductal Adenocarcinoma ◽  
Cancer Stemness ◽  
The Past ◽  
Desmoplastic Stroma ◽  
Potential Factors ◽  
Evolving Models

Pancreatic ductal adenocarcinoma (PDAC) is a devastating and highly aggressive malignancy. Existing therapeutic strategies only provide a small survival benefit in patients with PDAC. Laboratory and clinical research have identified various populations of stem-cell-like cancer cells or cancer stem cells (CSCs) as the driving force of PDAC progression, treatment-resistance, and metastasis. Whilst a number of therapeutics aiming at inhibiting or killing CSCs have been developed over the past decade, a series of notable clinical trial setbacks have led to their deprioritization from the pipelines, triggering efforts to refine the current CSC model and exploit alternative therapeutic strategies. This review describes the current and the evolving models of pancreatic CSCs (panCSCs) and the potential factors that hamper the clinical development of panCSC-targeted therapies, emphasizing the heterogeneity, the plasticity, and the non-binary pattern of cancer stemness, as well as the desmoplastic stroma impeding drug penetration. We summarized novel and promising therapeutic strategies implicated by the works of our groups and others’ that may overcome these hurdles and have shown efficacies in preclinical models of PDAC, emphasizing the unique advantages of targeting the stroma-engendered panCSC-niches and metronomic chemotherapy. Finally, we proposed feasible clinical trial strategies and biomarkers that can guide the next-generation clinical trials.

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