We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in ...severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches.
HER2-positive breast cancers may lose HER2 expression in recurrences and metastases. In this work, we studied cell lines derived from two transgenic mammary tumors driven by human HER2 that showed ...different dynamics of HER2 status. MamBo89HER2
cell line displayed high and stable HER2 expression, which was maintained upon in vivo passages, whereas MamBo43HER2
cell line gave rise to HER2-negative tumors from which MamBo38HER2
cell line was derived. Both low-density seeding and in vitro trastuzumab treatment of MamBo43HER2
cells induced the loss of HER2 expression. MamBo38HER2
cells showed a spindle-like morphology, high stemness and acquired in vivo malignancy. A comprehensive molecular profile confirmed the loss of addiction to HER2 signaling and acquisition of an EMT signature, together with increased angiogenesis and migration ability. We identified PDGFR-B among the newly expressed determinants of MamBo38HER2
cell tumorigenic ability. Sunitinib inhibited MamBo38HER2
tumor growth in vivo and reduced stemness and IL6 production in vitro. In conclusion, HER2-positive mammary tumors can evolve into tumors that display distinctive traits of claudin-low tumors. Our dynamic model of HER2 status can lead to the identification of new druggable targets, such as PDGFR-B, in order to counteract the resistance to HER2-targeted therapy that is caused by HER2 loss.
Myxofibrosarcoma is a rare malignant soft tissue sarcoma characterised by multiple local recurrence and can become of higher grade with each recurrence. Consequently, myxofibrosarcoma represents a ...burden for patients, a challenge for clinicians, and an interesting disease to study tumour progression. Currently, few myxofibrosarcoma preclinical models are available.
In this paper, we present a spontaneously immortalised myxofibrosarcoma patient-derived cell line (MF-R 3). We performed phenotypic characterization through multiple biological assays and analyses: proliferation, clonogenic potential, anchorage-independent growth and colony formation, migration, invasion, AgNOR staining, and ultrastructural evaluation.
MF-R 3 cells match morphologic and phenotypic characteristics of the original tumour as 2D cultures, 3D aggregates, and on the chorioallantoic membrane of chick embryos. Overall results show a clear neoplastic potential of this cell line. Finally, we tested MF-R 3 sensitivity to anthracyclines in 2D and 3D conditions finding a good response to these drugs.
In conclusion, we established a novel patient-derived myxofibrosarcoma cell line that, together with the few others available, could serve as an important model for studying the molecular pathogenesis of myxofibrosarcoma and for testing new drugs and therapeutic strategies in diverse experimental settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
(1) Background: This retrospective study aimed to analyze the history and treatment outcomes of localized, high-grade MLS of the extremities. (2) Methods: We retrospectively reviewed 82 patients with ...primary high-grade MLS of the extremities. OS, LRFS, MFS, PRS, and DFS were analyzed. (3) Results: Five-year OS and LRS were 96% (95% CI: 86-98) and 94% (95% CI: 85-98), respectively. Statistical analysis indicated no risk factors for OS and LFRS. MFS was 77% (65-85) at 5-year follow-up. Size (
= 0.0337) was the only risk factor statistically significant for MFS (HR = 0.248, 95% CI: 0.07-0.84). Median PRS after distant metastasis was 34 months (range: 1-127 months). Five-year PRS was 79% (48-93). Overall, the 5-year DFS was 76% (65-85). (4) Conclusions: Patients with MLS were found to have a good prognosis. In high-grade deep-seated tumors, common risk factors for MLS do not correlate with survival. Tumor size appears to be the only predictor of long-term DSF and MSF.
This case study focuses on scapula reconstruction using three-dimensional printing in a patient with low-grade osteosarcoma. Malignant tumors originating from the scapula often lead to destructive ...surgery, with poor functional status and quality of life for the patients. Using custom prosthetic technology through three-dimensional printing could be a possible solution for reconstruction with greater long-term functional outcomes. This study aims to assess the functional outcomes of the reconstruction. A 39-year-old patient with low-grade central osteosarcoma involving the lateral two-thirds of the scapula underwent a custom prosthetic reconstruction. The patient subsequently followed a rehabilitation protocol for 12 months. The results indicate that even though there was a slight decrease in the range of movement, and an increase in the disabilities of the arm, shoulder, and hand (DASH) score, no relevant increase in activities of daily living (ADL) disability was present at follow-up. The patient returned to carry out his daily activities without pain and with a minimal functional reduction in movement. In conclusion, three-dimensional prosthetic reconstruction is a valid alternative for scapula reconstruction, allowing excellent functional and aesthetic results in oncological cases.
(1) Background: Histological diagnosis and tumor grading are major prognostic and predictive factors in soft tissue sarcomas (STS), as they dictate the treatment strategies with a direct impact on ...patient survival. This study aims to investigate the grading accuracy, sensitivity, and specificity of Tru-Cut
biopsy (TCB) in primary localized myxoid liposarcomas (MLs) of the extremities and its impact on patient prognosis. (2) Methods: Patients with ML undergoing TCB and a subsequent tumor resection between 2007 and 2021 were evaluated. Concordance between the preoperative assessment and definitive histology was calculated with a weighted Cohen's kappa coefficient. Sensitivity, specificity, and diagnostic accuracy were calculated. (3) Results: Of 144 biopsies, the histological grade concordance rate was 63% (Kappa 0.2819). Neoadjuvant chemotherapy and/or radiotherapy impacted concordance with a downgrading effect in high-grade tumors. Among forty patients not treated in neoadjuvant settings, the sensitivity of TCB was 57%, the specificity was 100%, and the overall predictive values of positive and negative TCB were 100% and 50%, respectively. Misdiagnosis did not impact overall survival. (4) Conclusions: TCB may underestimate ML grading due to tumor heterogeneity. Neoadjuvant ChT and/or radiotherapy are associated with pathological downgrading; however, discordance in diagnosis does not modify patient prognosis because systemic treatment decision-making also includes other variables.
Trends in Bone Metastasis Modeling Laranga, Roberta; Duchi, Serena; Ibrahim, Toni ...
Cancers,
08/2020, Letnik:
12, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Bone is one of the most common sites for cancer metastasis. Bone tissue is composed by different kinds of cells that coexist in a coordinated balance. Due to the complexity of bone, it is impossible ...to capture the intricate interactions between cells under either physiological or pathological conditions. Hence, a variety of in vivo and in vitro approaches have been developed. Various models of tumor–bone diseases are routinely used to provide valuable information on the relationship between metastatic cancer cells and the bone tissue. Ideally, when modeling the metastasis of human cancers to bone, models would replicate the intra-tumor heterogeneity, as well as the genetic and phenotypic changes that occur with human cancers; such models would be scalable and reproducible to allow high-throughput investigation. Despite the continuous progress, there is still a lack of solid, amenable, and affordable models that are able to fully recapitulate the biological processes happening in vivo, permitting a correct interpretation of results. In the last decades, researchers have demonstrated that three-dimensional (3D) methods could be an innovative approach that lies between bi-dimensional (2D) models and animal models. Scientific evidence supports that the tumor microenvironment can be better reproduced in a 3D system than a 2D cell culture, and the 3D systems can be scaled up for drug screening in the same way as the 2D systems thanks to the current technologies developed. However, 3D models cannot completely recapitulate the inter- and intra-tumor heterogeneity found in patients. In contrast, ex vivo cultures of fragments of bone preserve key cell–cell and cell–matrix interactions and allow the study of bone cells in their natural 3D environment. Moreover, ex vivo bone organ cultures could be a better model to resemble the human pathogenic metastasis condition and useful tools to predict in vivo response to therapies. The aim of our review is to provide an overview of the current trends in bone metastasis modeling. By showing the existing in vitro and ex vivo systems, we aspire to contribute to broaden the knowledge on bone metastasis models and make these tools more appealing for further translational studies.
Bone is the third most frequent site of metastasis, with a particular incidence in breast and prostate cancer patients. For example, almost 70% of breast cancer patients develop several bone ...metastases in the late stage of the disease. Bone metastases are a challenge for clinicians and a burden for patients because they frequently cause pain and can lead to fractures. Unfortunately, current therapeutic options are in most cases only palliative and, although not curative, surgery remains the gold standard for bone metastasis treatment. Surgical intervention mostly provides the replacement of the affected bone with a bioimplant, which can be made by materials of different origins and designed through several techniques that have evolved throughout the years simultaneously with clinical needs. Several scientists and clinicians have worked to develop biomaterials with potentially successful biological and mechanical features, however, only a few of them have actually reached the scope. In this review, we extensively analyze currently available biomaterials-based strategies focusing on the newest and most innovative ideas while aiming to highlight what should be considered both a reliable choice for orthopedic surgeons and a future definitive and curative option for bone metastasis and cancer patients.
Homozygous knockout of p53 in mice leads to early mortality from lymphoma, with almost complete penetrance, thus hampering studies of other tumor histotypes related to p53 alterations. To avoid ...lymphoma development, we crossed p53 knockout mice (BALB-p53 mice) with alymphocytic BALB/c Rag2-/-;Il2rg-/- (RGKO) mice. We compared the tumor spectrum of homozygous (BALB-p53-/-) and heterozygous (BALB-p53+/-) mice with alymphocytic mice (RGKO-p53-/- and RGKO-p53+/-). Lymphoma incidence in BALB-p53-/- mice exceeded 80%, whereas in RGKO-p53-/- it was strongly reduced. The prevalent tumor of RGKO-p53-/- mice was hemangiosarcoma (incidence over 65% in both sexes, mean latency 18 weeks), other tumors included soft tissue sarcomas (incidence ~10%), lung and mammary carcinomas. Tumor spectrum changes occurred also in p53 heterozygotes, in which lymphomas are relatively rare (~20%). RGKO-p53+/- had an increased incidence of hemangiosarcomas, reaching ~30%, and females had an increased incidence of osteosarcomas, reaching ~20%. Osteosarcomas shared with the corresponding human tumors the involvement of limbs and a high metastatic ability, mainly to the lungs. Specific alterations in the expression of p53-related genes (p16Ink4a, p19Arf, p15Ink4b, p21Cip1) were observed. Genetic prevention of lymphoma in p53 knockout mice led to new models of sarcoma development, available for studies on hemangiosarcoma and osteosarcoma onset and metastatization.
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