Primary cancer-associated fibroblasts exhibit high heterogeneity among breast cancer subtypes

Piwocka, Oliwia; Musielak, Marika; Piotrowski, Igor; Kulcenty, Katarzyna; Adamczyk, Beata; Fundowicz, Magdalena; Suchorska, Wiktoria; Malicki, J.

doi:10.5603/rpor.a2023.0026

Cited by 7 publications

(5 citation statements)

References 22 publications

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“…The isolated cells were stained for cell viability using a Live/Dead Blue cell stain (L34962, Thermo Fisher Scientific, Waltham, MA, USA) and blocked with 4% bovine serum albumin (BSA). Counting beads were added to each sample and a minimum 10,000 events were acquired by BD FACS Fortessa (BD Biosciences, San Jose, CA, USA) as previously described [21][22][23][24]. The data was analyzed with FlowJo program v10 (BD Biosciences, San Jose, CA, USA).…”

Section: Tumor Progression and Drug Resistance In Physiologically Rel...mentioning

confidence: 99%

“…Unfortunately, the effects of CAFs and normal fibroblasts in OC progression and drug resistance are significantly different [17][18][19][20] , making normal fibroblasts a less ideal source. Alternatively, primary CAFs can be isolated from tumors and cultured in vitro, but their lifespan is finite; they have shown limited expansion capacity and the use of cells from different patients can result in non-reproducible results associated with the technologies and methodologies from each laboratory, and the lack of characterization, and heterogeneity between patients [21][22][23] . Therefore, there is a need to establish protocols that allow for the reprogramming of normal fibroblasts into CAFs with a reproducible, cost-effective, and clinically relevant approach.…”

Section: Introductionmentioning

confidence: 99%

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Normal Uterine Fibroblast Are Reprogramed into Ovarian Cancer-Associated Fibroblasts by Ovarian Tumor-derived Conditioned Media

Axemaker,

Plesselova,

Calar

et al. 2023

Preprint

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SUMMARYCancer-associated fibroblasts (CAFs) are key contributors to ovarian cancer (OC) progression and therapeutic resistance through dysregulation of the extracellular matrix (ECM). CAFs are a heterogenous population derived from different cell types through activation and reprogramming. Current studies rely on uncharacterized heterogenous primary CAFs or normal fibroblasts that fail to recapitulate CAF-like tumor behavior. Here, we present a translatable-based approach for the reprogramming of normal uterine fibroblasts into ovarian CAFs using ovarian tumor-derived conditioned media to establish two well-characterized ovarian conditioned CAF lines. Phenotypic and functional characterization demonstrated that the conditioned CAFs expressed a CAF-like phenotype, strengthened proliferation, secretory, contractility, and ECM remodeling properties when compared to resting normal fibroblasts, consistent with an activated fibroblast status. Moreover, conditioned CAFs significantly enhanced drug resistance and tumor progression and resembled a CAF-like subtype associated with worse prognosis. The present study provides a reproducible, cost-effective, and clinically relevant protocol to reprogram normal fibroblasts into CAFs using tumor-derived conditioned media. Using these resources, further development of therapeutics that possess potentiality and specificity towards CAF-mediated chemoresistance in OC are further warranted.

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Section: Tumor Progression and Drug Resistance In Physiologically Rel...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Normal Uterine Fibroblast Are Reprogramed into Ovarian Cancer-Associated Fibroblasts by Ovarian Tumor-derived Conditioned Media

Axemaker,

Plesselova,

Calar

et al. 2023

Preprint

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show abstract

“…Lineage-dependent heterogeneity is attributed to the numerous potential sources of CAFs as previously mentioned. Interaction of CAFs with the tumor cells and other stromal cells also results in a change in molecular expression and function over time, resulting in spatial and temporal heterogeneity [115,118]. Amongst all these CAF surface receptors, the most relevant in oncology and nuclear medicine has been fibroblast activated protein (FAP) [113].…”

Section: Cancer-associated Fibroblasts (Caf) and Fibroblast Activated...mentioning

confidence: 99%

Imaging Molecular Targets and Metabolic Pathways in Breast Cancer for Improved Clinical Management: Current Practice and Future Perspectives

Ndlovu,

Lawal,

Mokoala

et al. 2024

IJMS

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Breast cancer is the most frequently diagnosed cancer and leading cause of cancer-related deaths worldwide. Timely decision-making that enables implementation of the most appropriate therapy or therapies is essential for achieving the best clinical outcomes in breast cancer. While clinicopathologic characteristics and immunohistochemistry have traditionally been used in decision-making, these clinical and laboratory parameters may be difficult to ascertain or be equivocal due to tumor heterogeneity. Tumor heterogeneity is described as a phenomenon characterized by spatial or temporal phenotypic variations in tumor characteristics. Spatial variations occur within tumor lesions or between lesions at a single time point while temporal variations are seen as tumor lesions evolve with time. Due to limitations associated with immunohistochemistry (which requires invasive biopsies), whole-body molecular imaging tools such as standard-of-care [18F]FDG and [18F]FES PET/CT are indispensable in addressing this conundrum. Despite their proven utility, these standard-of-care imaging methods are often unable to image a myriad of other molecular pathways associated with breast cancer. This has stimulated interest in the development of novel radiopharmaceuticals targeting other molecular pathways and processes. In this review, we discuss validated and potential roles of these standard-of-care and novel molecular approaches. These approaches’ relationships with patient clinicopathologic and immunohistochemical characteristics as well as their influence on patient management will be discussed in greater detail. This paper will also introduce and discuss the potential utility of novel PARP inhibitor-based radiopharmaceuticals as non-invasive biomarkers of PARP expression/upregulation.

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“…On the other hand, CAFs support ECM remodeling and create supportive environment for cancer cells (CCs) (Chhabra and Weeraratna, 2023). Most CAFs originate from various cells or become activated from a quiescent state ( Piwocka et al, 2023 ). The best-described pathway of CAF derival is through the interaction of NFs with CCs that secrete cytokines and growth factors that impact fibroblast phenotype.…”

Section: Introductionmentioning

confidence: 99%

Dynamic interactions in the tumor niche: how the cross-talk between CAFs and the tumor microenvironment impacts resistance to therapy

Piwocka,

Piotrowski,

Suchorska

et al. 2024

Front. Mol. Biosci.

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The tumor microenvironment (TME) is a complex ecosystem of cells, signaling molecules, and extracellular matrix components that profoundly influence cancer progression. Among the key players in the TME, cancer-associated fibroblasts (CAFs) have gained increasing attention for their diverse and influential roles. CAFs are activated fibroblasts found abundantly within the TME of various cancer types. CAFs contribute significantly to tumor progression by promoting angiogenesis, remodeling the extracellular matrix, and modulating immune cell infiltration. In order to influence the microenvironment, CAFs engage in cross-talk with immune cells, cancer cells, and other stromal components through paracrine signaling and direct cell-cell interactions. This cross-talk can result in immunosuppression, tumor cell proliferation, and epithelial-mesenchymal transition, contributing to disease progression. Emerging evidence suggests that CAFs play a crucial role in therapy resistance, including resistance to chemotherapy and radiotherapy. CAFs can modulate the tumor response to treatment by secreting factors that promote drug efflux, enhance DNA repair mechanisms, and suppress apoptosis pathways. This paper aims to understand the multifaceted functions of CAFs within the TME, discusses cross-talk between CAFs with other TME cells, and sheds light on the contibution of CAFs to therapy resistance. Targeting CAFs or disrupting their cross-talk with other cells holds promise for overcoming drug resistance and improving the treatment efficacy of various cancer types.

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Primary cancer-associated fibroblasts exhibit high heterogeneity among breast cancer subtypes

Cited by 7 publications

References 22 publications

Normal Uterine Fibroblast Are Reprogramed into Ovarian Cancer-Associated Fibroblasts by Ovarian Tumor-derived Conditioned Media

Normal Uterine Fibroblast Are Reprogramed into Ovarian Cancer-Associated Fibroblasts by Ovarian Tumor-derived Conditioned Media

Imaging Molecular Targets and Metabolic Pathways in Breast Cancer for Improved Clinical Management: Current Practice and Future Perspectives

Dynamic interactions in the tumor niche: how the cross-talk between CAFs and the tumor microenvironment impacts resistance to therapy

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