Regional and temporal heterogeneity of epithelial ovarian cancer tumor biopsies: implications for therapeutic strategies.
Ontology highlight
ABSTRACT:
SUBMITTER: Paracchini L
PROVIDER: S-EPMC8629406 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Epithelial ovarian cancer (EOC) is a leading cause of cancer death in women. Standard of care treatment has remained platinum-containing cytotoxic chemotherapy for over three decades. Among the central challenges in treating ovarian CA are disease recurrence and the development of chemoresistance. Survival is uniformly poor for patients with chemoresistant recurrent disease and effective therapeutic options are limited. As such, delineating the mechanisms of chemoresistance and developing targeted therapies to prevent chemoresistance from occurring are of vital importance to improving survival for patients with EOC. Attempts to characterize mechanisms of chemoresistance have implicated numerous cellular pathways, but a rift remains between pre-clinical findings and translation to improving patient survival. More recently, the interplay among different cell types within the tumor microenvironment has become central to understanding how chemoresistance may develop and may be sustained. An improved understanding of how tumor cell-intrinsic and -extrinsic pathways converge during the development of chemoresistance may improve the likelihood of successful clinical translation. This review focuses on the roles of the EOC tumor microenvironment and tumor cell heterogeneity in the development of chemoresistance. We review recent studies into mechanisms of chemoresistance as they relate to tumor microenvironment and development of novel therapeutic approaches that exploit these mechanisms to prevent or reverse chemoresistance. This review attempts to cast these latest discoveries in a clinical context by summarizing trends in ongoing clinical trials for patients with EOC.
| S-EPMC7396799 | biostudies-literature
Project description:BACKGROUND:Epithelial ovarian cancer exhibits extensive interpatient and intratumoral heterogeneity, which can hinder successful treatment strategies. Herein, we investigated the efficacy of an emerging oncolytic, Maraba virus (MRBV), in an in vitro model of ovarian tumour heterogeneity. METHODS:Four ovarian high-grade serous cancer (HGSC) cell lines were isolated and established from a single patient at four points during disease progression. Limiting-dilution subcloning generated seven additional subclone lines to assess intratumoral heterogeneity. MRBV entry and oncolytic efficacy were assessed among all 11 cell lines. Low-density receptor (LDLR) expression, conditioned media treatments and co-cultures were performed to determine factors impacting MRBV oncolysis. RESULTS:Temporal and intratumoral heterogeneity identified two subpopulations of cells: one that was highly sensitive to MRBV, and another set which exhibited 1000-fold reduced susceptibility to MRBV-mediated oncolysis. We explored both intracellular and extracellular mechanisms influencing sensitivity to MRBV and identified that LDLR can partially mediate MRBV infection. LDLR expression, however, was not the singular determinant of sensitivity to MRBV among the HGSC cell lines and subclones. We verified that there were no apparent extracellular factors, such as type I interferon responses, contributing to MRBV resistance. However, direct cell-cell contact by co-culture of MRBV-resistant subclones with sensitive cells restored virus infection and oncolytic killing of mixed population. CONCLUSIONS:Our data is the first to demonstrate differential efficacy of an oncolytic virus in the context of both spatial and temporal heterogeneity of HGSC cells and to evaluate whether it will constitute a barrier to effective viral oncolytic therapy.
| S-EPMC5577660 | biostudies-literature
Project description:Macrophages are heterogeneous cells that present as different functional phenotypes due to their plasticity. They can be classified into two categories, namely M1- and M2-like macrophages, which are involved in processes as diverse as anti-tumor activity and immunosuppressive tumor promotion. Tumor-associated macrophages (TAMs) are defined as being of an M2-type and are considered as the active component in tumor microenvironment. TAMs are involved in multiple processes of tumor progression through the expression of cytokines, chemokines, growth factors, protein hydrolases and more, which lead to enhance tumor cell proliferation, angiogenesis, and immunosuppression, which in turn supports invasion and metastasis. It is assumed that the abundance of TAMs in major solid tumors is correlated to a negative patient prognosis. Because of the currently available data of the TAMs' role in tumor development, these cells have emerged as a promising target for novel cancer treatment strategies. In this paper, we will briefly describe the origins and types of TAMs and will try to comprehensively show how TAMs contribute to tumorigenesis and disease progression. Finally, we will present the main TAM-based therapeutic strategies currently available.
| S-EPMC8715617 | biostudies-literature
Project description:Epithelial ovarian cancer (EOC) affects 43,000 women worldwide every year and has a five-year survival rate of 30%. Mainstay treatment is extensive surgery and chemotherapy. Outcomes could be improved by molecular profiling. We conducted a review of the literature to identify relevant publications on molecular and genetic alterations in EOC. Approximately 15% of all EOCs are due to BRCA1 or BRCA2 mutations. Four histologic subtypes characterized by different mutations have been described: serous, endometrioid, mucinous, and clear-cell. Between 20-30% of high-grade serous EOCs have a BRCA mutation. Tumors with BRCA mutations are unable to repair double-strand DNA breaks, making them more sensitive to platinum-based chemotherapy and to PolyAdenosine Diphosphate-Ribose Polymerase (PARP) inhibitors. Olaparib is a PARP inhibitor with proven efficacy in BRCA-mutated ovarian cancer, but its effectiveness remains to be demonstrated in tumors with a BRCAness (breast cancer) profile (i.e., also including sporadic tumors in patients with deficient DNA repair genes). A universally accepted molecular definition of BRCAness is required to identify optimal theranostic strategies involving PARP inhibitors. Gene expression analyses have led to the identification of four subgroups of high-grade serous EOC: mesenchymal, proliferative, differentiated, and immunoreactive. These subtypes are not mutually exclusive but are correlated with prognosis. They are not yet used in routine clinical practice. A greater understanding of EOC subtypes could improve patient management.
| S-EPMC7408825 | biostudies-literature
Project description:Metabolic dysregulation in the tumor microenvironment has significant impact on immune infiltration and immune responses. However, interaction between immunity and metabolism in the ovarian microenvironment requires further exploration. We constructed an immunometabolism gene set and ovarian cancer cohort from The Cancer Genome Atlas (TCGA) and classified these into three immunometabolism subtypes. We explored the relationships between immune infiltration and metabolic reprogramming. Additionally, we built risk score and nomogram as prognostic signatures. Three distinctive immunometabolism subtypes were identified with therapeutic and prognostic implications. Subtype 1, the "immune suppressive-glycan metabolism subtype," featured high levels of immunosuppressive cell infiltration and glycan metabolism activation; Subtype 2, the "immune inflamed-amino acid metabolism subtype," showed abundant adaptive immune cell infiltration and amino acid metabolism activation; Subtype 3, the "immune desert-endocrine subtype," was characterized by low immune cell infiltration and upregulation of hormone biosynthesis. Furthermore, we found that epinephrine biosynthesis displayed a significantly negative correlation with MHC molecules, which may result in defective antigen presentation. We proposed immunometabolism subtypes with prognostic implications and provided new perspectives for the ovarian cancer microenvironment.
| S-EPMC8008085 | biostudies-literature
Project description:Over the last decade, the treatment of metastatic melanoma has been revolutionized by the translation of molecular insights into therapeutic benefit for patients. These include advances in immunotherapeutic and small-molecule approaches aimed at destroying cells with immunogenic antigens or gene mutations. Despite these advances, the limited durability of clinical response and eventual disease progression underscores a need for better understanding of mechanisms underlying tumor development. Current targeted therapies are developed partly based on the rationale that tumors are primarily clonal with respect to mutant oncogene or cell surface antigen target. However, with the advancement of cell isolation and transplantation approaches coupled with deep sequencing and mutation detection techniques, it has become increasingly clear that tumors are polyclonal. As a result, sensitive malignant cells are eradicated by treatment while the remaining tumor cell populations are conferred varying degrees of resistance and survival advantages by harbouring or acquiring certain epigenetic and genetic abnormalities. Tumor heterogeneity thus represents a major obstacle to the successful application of current therapies. Gaining insights into the cellular and molecular aspects of tumor diversity will not only facilitate the development and selection of therapeutic targets but also promote the evolution of precision medicine. In this viewpoint, we will discuss the implications of tumor heterogeneity for the treatment of metastatic melanoma and propose approaches to accelerate the translation of scientific discovery into improved clinical outcomes.
| S-EPMC4972498 | biostudies-literature
Project description:Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted.
| S-EPMC6429294 | biostudies-literature
Project description:Advances in next-generation sequencing and bioinformatics have led to an unprecedented view of the cancer genome and its evolution. Genomic studies have demonstrated the complex and heterogeneous clonal landscape of tumors of different origins and the potential impact of intratumor heterogeneity on treatment response and resistance, cancer progression, and the risk of disease relapse. However, the significance of subclonal mutations, in particular mutations in driver genes, and their evolution through time and their dynamics in response to cancer therapies, is yet to be determined. The necessary tools are now available to prospectively determine whether clonal heterogeneity can be used as a biomarker of clinical outcome and to what extent subclonal somatic alterations might influence clinical outcome. Studies that use longitudinal tissue sampling, integrating both genomic and clinical data, have the potential to reveal the subclonal composition and track the evolution of tumors to address these questions and to begin to define the breadth of genetic diversity in different tumor types and its relevance to patient outcome. Such studies may provide further evidence for drug-resistance mechanisms informing combinatorial, adaptive, and tumor immune therapies placed within the context of tumor evolution.
| S-EPMC4374162 | biostudies-literature
Project description:The rapidly changing landscape of oncology has brought new light, and with it, new challenges to optimizing therapeutic strategies for patients. Although the concept of patient heterogeneity is well known to any practicing clinician, a more detailed understanding of the biologic changes that underscore the clinical picture is beginning to emerge. Thus, tumor heterogeneity has come to encompass more than just the clinical picture and can represent both intratumor and intertumor differences. Within the fields of thoracic oncology and melanoma, the discovery of key molecular drivers has resulted in landmark breakthroughs in therapy. However, the complexities of tumor genetics and the interaction within the environment continue to drive the search for better therapies. Ongoing challenges include the accurate and timely assessment of genetic changes as well as the development of resistance and the resultant compensatory mechanisms. Novel technologies, including commercially available next-generation sequencing, have allowed for a greater breadth and depth of information to be gained from a single pathologic specimen, and it is now being incorporated into routine clinical practice. Translational advances have subsequently provided valuable insight into mechanisms of resistance, with the development of novel treatment strategies. Future work will focus on novel diagnostic techniques and adaptive mechanisms that can ultimately drive the development of the next generation of cancer therapy.
| S-EPMC10132823 | biostudies-literature
Project description:RationaleExcessive deposition of extracellular matrix occurs in proximal airways of individuals with asthma, but fibrosis in distal lung has not been observed. Whether differing fibrotic capacities of fibroblasts from these two regions contribute to this variability is unknown.ObjectivesWe compared morphologic and functional characteristics of fibroblasts isolated from proximal airways and distal lung parenchyma to determine phenotypic differences.MethodsConcurrent proximal airway and distal lung biopsies were obtained by bronchoscopy from subjects with asthma to isolate airway and distal lung fibroblasts, respectively. The following characteristics were compared: morphology, proliferation, alpha-smooth muscle actin expression, and synthesis of procollagen type I and eotaxin-1.ResultsAirway fibroblasts (AFs) are morphologically distinct from distal lung fibroblasts (DLFs): they are larger (2.3-fold greater surface area vs. matched DLFs; p = 0.02), stellate in appearance, and with more cytoplasmic projections compared with the spindle-shaped DLFs. AFs synthesized more procollagen type I than did DLFs at baseline (twofold higher; p = 0.003) and after transforming growth factor-beta stimulation (1.4-fold higher; p = 0.02). Similarly, AFs produced more eotaxin-1 than did DLFs at baseline (2.5-fold higher; p = 0.004) and after interleukin-13 stimulation (13-fold higher; p = 0.0001). In contrast, DLFs proliferate more than AFs with serum stimulation (about sixfold greater; p = 0.03). Unstimulated DLFs also expressed more alpha-smooth muscle actin than did corresponding AFs (p = 0.006).ConclusionsThese studies suggest that at least two phenotypes of fibroblast exist in the lung. These phenotypic differences may partially explain the variable responses to injury and repair between proximal airways and distal lung/parenchyma in asthma and other respiratory diseases.
| S-EPMC2662967 | biostudies-literature