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At least 19 recordsLinked to original sources
PubMed1979

Ganglioside patterns of metastatic and non-metastatic transplantable hepatocellular carcinomas of the rat.

In previous investigations, we correlated levels of sialic acid, gangliosides, and ganglioside glycosyltransferases with tumorigenesis over a 24-week continuum of growth of hepatocellular neoplasms of the rat induced by the carcinogen N-2-fluorenylacetamide. However, metastatic tumors developed only rarely and were not analyzed. To investigate surface changes associated with metastasis, well-differentiated and poorly differentiated hepatocellular carcinomas were transplanted to syngeneic recipient rats. From those, several metastatic and nonmetastatic isolates were obtained and compared. Both total and ganglioside sialic acid amounts in transplantable hepatomas were elevated above control liver values but were significantly lower for metastatic lines than for nonmetastatic lines. The nonmetastatic lines were characterized by ganglioside patterns depleted in the precursor ganglioside GM3 (sialic acid-galactose-glucose-ceramide) and elevated in the products of the monosialoganglioside pathway. In contrast, metastatic isolates exhibited a restoration of GM3 and nearer normal amounts of other gangliosides. The findings point to differences in sialic acid-containing glycolipids, comparing metastatic and nonmetastatic hepatocellular carcinomas, and further extend the concept that ganglioside alterations do not cause tumorigenesis but are the end result of a cascade of events which apparently continue beyond the onset of metastasis.

2-Acetylaminofluorene↗
PubMed1975

Carcinoma metastatic to the eye and orbit II. A clinicopathological study of 26 patients with carcinoma metastatic to the anterior segment of the eye.

In 26 of 227 patients with carcinoma metastatic to the eye or orbit, metastasis to the anterior uveal tract was the predominating feature. There was a definite propensity for the tumor to involve the horizontal meridian of the iris or ciliary body, rather than the upper or lower portions. The site of the primary tumor in the 26 patients was as follows: lung 14; breast, 9; kidney, 2; and rectum, 1. Ocular symptoms and signs produced by the metastatic tumors at onset or during the course of the disease included decreased vision (80%), a visible mass (72%), redness of the eye (56%), pain (56%), glaucoma (56%), iridocylitis (44%), and hyphema (24%). The median survival of the 26 patients with metastasis to the anterior segment of the eye was only 5.4 months from the time of ocular surgery. This is poorer than the median survival (7.2 months) of the patients with metastasis confined to the posterior segment, and much worse than the median survival (15.6 months) of the 28 patients with orbital involvement.

Adenocarcinoma↗
PubMed2025

Diffusely metastatic glioblastoma with FGFR3::TACC3 fusion: cell-free DNA fragmentation analyses and molecular characterization of matched primary and metastatic tumor sites.

Extracranial metastasis of IDH-wildtype glioblastoma is very rare and poorly understood at the molecular level. We report a case of FGFR3::TACC3 fusion IDH-wildtype glioblastoma in a 61-year-old male, whose preoperative blood sample showed highly aberrant cfDNA fragmentation patterns, which could be suggestive of early systemic dissemination, undetected by standard-of-care imaging of his body. Eleven months post-resection and adjuvant therapy, he developed widespread extracranial metastases. Comprehensive molecular profiling of matched primary and metastatic tumors revealed broadly conserved genomic, transcriptomic, and copy number landscapes, with the metastasis harboring an additional ERCC6 deletion and enriched expression of receptor tyrosine kinase signaling genes. These findings provide rare insight into the genetic continuity and evolution underlying IDH-wildtype glioblastoma metastasis.

Humans↗
PubMed1979

[Studies on biological characterization of mammary tumours of the Sprague-Dawley-rat in the syngeneic tumour-host system. III. Metastatic experiments with primary tumours, transplantation passages and metastatic cells (author's transl)].

The metastatic spread following intravenous application of cells from primary and transplanted mammary carcinomas is described. When using cells from primary tumours the incidence rate was between 0 and 17%, but was much higher in the case of advanced tumours (transplantation passages and metastases).

Animals↗
PubMed1975

Types of reaction in the regional lymph nodes in non-metastatic and minute-metastatic carcinoma of the uterine cervix.

The authors studied tissue reactions in the regional lymph nodes of 68 patients with an invasive cancer of the uterine cervix at stage I and II of neoplastic disease. Two basic types of the lymph nodes reactions have been distinguished. In the first type of changes a reactive hyperplasia of sinusoidal histiocytosis predominated, as well as distinct activation of lymphocyte production within the follicles and numerous aggregates of plasmacytoid cells within the medullary cords. The second type of reaction was characterised by fibroplastic reaction causing constriction and block of capsular lymphatic and blood vessels, the pseudotransformation into hemolymph node and hematoxyphilic atrophy of lymphoreticular tissue. The authors' observations indicate that in case with the predominance of the second type reaction within regional lymph nodes arise favourable conditions for the production of distant metastases.

Adenocarcinoma↗
PubMed1979

Cell surface sialylation of glycoproteins and glycosphingolipids in cultured metastatic variant RNA-virus transformed non-producer BALB/c 3T3 cell lines.

The sialic acid composition and the display of cell surface sialyl components of several metastatic variant RNA-virus-transformed non-producer BALB/c 3T3 have been studied in culture. The following observations have been made concerning the sialyl components in these lines: (1) the compositions of whole-cell total, protein-bound and lipid-bound sialic acid were not appreciably different; (2) the surface sialic acid studied using the neuraminidase-galactose oxidase method and metabolic labelling followed by neuraminidase hydrolysis showed a positive correlation with the metastatic properties of these lines; (3) the degree of surface sialylation determined by galactose oxidase--sodium borotritide labelling of neuraminidase-treated and untreated cells revealed that 44--89% of exposed galactose and/or N-acetyl galactosamine residues of total cell-surface saccharides were sialylated in highly and intermediately metastatic lines as compared with 11-30% in the poorly and non-metastatic lines; (4) the cell surface glycoproteins and glycosphingolipids contributed equally well in their degree of sialylation and there was a positive correlation with the metastatic properties of the cells in vivo; (5) the cell surface proteins labelled by the lactoperoxidase-catalyzed iodination technique, followed by gel electrophoresis, showed some minor differences between metastatic variant lines. However, glycoproteins detected by the galactose oxidase labelling of neuraminidase-treated and untreated cells showed major differences in composition between the metastatic variant lines. The study of four highly metastatic lines has shown that the cells of these lines were enriched in several sialyl-glycoproteins, whereas three non tumorigenic lines and two poorly metastatic or non-metastatic lines contained unsialylated glycoproteins. The results indicate an enhancement of the degree of sialylation of surface glycoconjugates accompanying the metastatic process in RNA-virus-transformed mouse lines.

Animals↗
PubMed1979

Introduction of metastatic heterogeneity by short-term in vivo passage of a cloned transformed cell line.

An experimental system for the study of metastasis has been developed using an epithelioid cell line of hepatic origin which had previously been chemically transformed in vitro. These metastatic cells were studied in the syngeneic rat strain. The cloned parent cell line metastasizes only to the lungs following intravenous, subcutaneous, or intraperitoneal injection. The metastatic phenotype is stable during in vitro passage, and subclones from the parent clone have a metastatic capacity statistically similar to that of the parent clone. Following ascites passage of the parent cell line, the cell population obtained exhibits the same metastatic ability as the parent clone. However, subclones obtained from the ascites-passaged population exhibit metastatic heterogeneity. This heterogeneity is introduced by the host passage and not by in vitro culture or subcloning. In the case of the two metastatic variants examined, the difference in the metastatic phenotype is found not to be due to differences in arrest or trapping of the cells but appears to be related to long-term survival and proliferation of the tumor cells following their arrest in the lungs. Morphologically the variants are very similar, and growth of the metastatic foci provokes a vigorous inflammatory response by the host.

Animals↗
PubMed1978

The lipid-chemical features of the metastatic tissues into the liver from the human gastric cancer, large intestinal cancer and malignant insulinoma.

In order to clarify the biochemical features of metastatic tissues into the liver of human cancerous cells, 12 of primary cancerous tissues and 3 of metastatic tissues of the large intestinal cancer, 6 of primary cancerous tissues and 2 of metastatic tissues of the gastric cancer, and 3 of primary cancerous tissues and 3 of metastatic tissues of malignant insulinoma were studied lipid-chemically. Cancerous tissues and metastatic tissues into the liver were collected by biopsy or surgical operation. From each tissue, the total lipid was extracted and one part of the total lipid was separated into phospholipid and triglyceride by TLC. Then, the fatty acid composition and the fatty acid content of each lipid fraction were measured by GLC. The most remarkable findings were recognized in the phospholipid fatty acid composition of the tissues. Namely, the percentage values of C14:0 and C16:1 were larger and that of C20:4 was smaller in metastatic tissues than those of gastric primary lesions. As for the large intestinal cancer, the percentage value of C18:1 was smaller and that of C18:2 larger in metastatic tissues than those of primary lesions. In the malignant insulinoma, the percentage value of C18:0 was larger in metastatic tissues than that of the primary lesions.

Adenoma, Islet Cell↗
PubMed2026

SPEN inactivation drives resistance to androgen receptor pathway inhibitors in metastatic prostate cancer.

PURPOSE: Treatment intensification with androgen receptor pathway inhibitors (ARPIs) has become the standard of care for patients with metastatic prostate cancer. However, there remains an unmet need to identify biomarkers for treatment resistance. Here, we identify SPEN inactivation as a driver of ARPI resistance. EXPERIMENTAL DESIGN: Pre-clinical studies were performed in LNCaP and VCaP cell lines. Data from a nationwide prostate cancer clinico-genomic database were extracted. Log-rank test and Cox proportional hazards models were used to compare time to next treatment (TTNT) on ARPI with/without SPEN mutations. SPEN immunohistochemistry was performed on a rapid autopsy metastatic tissue microarray. RESULTS: SPEN was identified as a top enzalutamide resistance hit in an unbiased genome-wide loss-of-function screen. SPEN inactivation results in upregulation of cell cycle proliferation and basal/stem cell activity as well as increased translation of pro-oncogenic genes. In a large patient cohort (N=6828), SPEN mutations are enriched following treatment with ARPIs (2.1% to 3.6%, p=0.001) and correlate with shorter TTNT on ARPI in patients with metastatic hormone-sensitive prostate cancer (6.4 vs 29.7 months, HR 2.67, p=0.02). In a metastatic rapid autopsy cohort (N=181), low SPEN H-score is associated with shorter time on abiraterone (5.0 vs 7.9 months, p=0.023) in metastatic castration-resistant prostate cancer. CONCLUSIONS: In real-world cohorts, loss of SPEN function across genomic, transcriptomic, and protein levels is associated with reduced benefit from ARPI therapy in metastatic prostate cancer. These findings identify SPEN inactivation as a clinically relevant biomarker of ARPI resistance that warrants prospective evaluation to guide treatment selection.

Journal Article↗
PubMed1979

A tumor-associated organ-specific antigen characteristic of spontaneously metastatic rat mammary carcinomas.

An organ-specific tumor-associated antigen (TAA) was present in several metastatic and nonmetastatic mammary carcinomas induced in WF female rats by 3-methylcholanthrene. The level of TAA was high in 2 metastatic carcinomas tested (TMT-081 and SMT-2A) and much lower--by a factor of 50--200--in 2 nonmetastatic mammary carcinomas (MT-100 and MT-W9B). The TAA in the 2 metastatic tumors was identical, as demonstrated by immunodiffusion and supported by cross-reactivity with antibody against TAA from TMT-081 in a binding inhibition radioimmunoassay. The TAA was shed in relatively large amounts by the metastatic tumors maintained in short-term organ culture. The high level and shedding of TAA thus appeared to be characteristics of the metastatic tumors but not of the nonmetastatic ones. This suggests that TAA on the cell membrane or in the circulation may be involved in the metastatic process as a factor blocking potentially cytotoxic cells or in other ways leading to suppression of the immune response against the tumor.

Animals↗
PubMed1979

Immunologic studies of membrane mutants of a highly metastatic murine tumor.

MDAY-D2 is a highly tumorigenic and anaplastic DBA/2 strain murine transplantable tumor capable of rapid and widespread spontaneous metastatic growth. It was therefore chosen as an ideal murine tumor model for the study of factors affecting metastatic growth. Two approaches were taken in an effort to obtain stable qualitative and quantitative low-metastatic variants of MDAY-D2, namely, cloning of multiple sublines and derivation of lectin-resistant (LecR) mutants. In the first method, 20 clones were isolated, and of these, three initially showed a marked reducstion in ability to metastasize from a subcutaneous site. However, these clones proved to be unstable both in vivo and in vitro. In the LecR selection experiments, 18 independent variants were obtained using chemical mutagenesis followed by treatment with wheat germ agglutinin (WGA), phytohemagglutinin (PHA), or concanavalin A (Con A). All of the variants proved to be highly metastatic except two WGAR variants, designated MDWI and MDW3. They proved to be nontumorigenic in normal DBA/2 hosts even when as many as 5 X 10(6) cells were injected, and this was found to be a stable change. Despite this fact, the nontumorigens an unchanged expression of H-2d and Ly-6.2 alloantigens and Fc receptors. The variants were, however, tumorigenic and metastatic in severely immunosuppressed (nude) mice, but not in moderately immunosuppressed 250-R-irradiated DBA/2 hosts. The results demonstrate that 1) stable membrane mutant sublines possessing radically altered growth properties in vivo can occasionally be obtained by selection of LecR variants, and 2) their growth and metastatic properties can be greatly affected by the immunologic status of the host. The possibility that the chemical mutagen treatment itself induced, or was responsible for, MDW1 and MDW3 variant formation is also discussed.

Animals↗
PubMed2026

Integrated clinicogenomic analysis reveals the evolution and metastatic tropisms of advanced colorectal cancer.

We performed an integrated clinical and genomic analysis of over 7,000 consecutively sequenced colorectal cancer (CRC) samples to comprehensively characterize genetic drivers and metastatic tropisms of CRC. We find that genomic evolutionary changes, such as clonal mutations and oncogenic mutant allelic imbalance, selectively enhance the impact of recurrent oncogenic alterations. We identify the relative timing of organ-specific metastasis, showing sequential metastatic progression in microsatellite stable CRC with brain and adrenal metastases as late events; metastatic sites that cluster together, such as lung, bone, and brain metastases; and genomic events that enhance or decrease risk for each metastatic site, with WNT pathway activation as overall protective while RAS pathway activation increased risk for spread to all metastatic sites. Our data suggest that despite the heterogeneity in CRC, genomic evolution increases the impact of recurrent alterations, and integrating information about tumor primary location and genomics can be used to predict organ-specific metastasis risk.

Humans↗
PubMed1978

Hormonal activation of adenylate cyclase in mouse melanoma metastatic variants.

The ability of melanocyte stimulating hormone (MSH), adrenocorticotropic hormone (ACTH), and prostaglandin E1 (PGE1) to stimulate the accumulation of cyclic AMP was examined in intact mouse melanoma cells of varying metastatic potential. F1 cells (low metastatic potential) had significantly greater cyclic AMP levels in response to all three hormones than F5 (intermediate metastatic potential) and F10 (high metastatic potential) cells. The ranking of the response was as follows: MSH, F1 greater than F5 greater than F10, ACTH, F1 greater than F5 greater F10, PGE, F1 greater than F10 greater F5. In contrast to the above, the degree of hormonal stimulation of adenylate cyclase in broken cell preparations was virtually identical in all three melanoma cell lines. Control enzyme activity was depressed in both F5 and F10 relative to F1. The conflicting results between studies of intact vs. broken cell preparations could not be explained by increased cyclic AMP phosphodiesterase activity in F5 and F10 cells. We conclude that as the melanoma cells increase in metastatic potential, there is a significant loss in the ability of their cyclic AMP system to respond appropriately to hormonal stimuli.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2026

The genomic landscape of HER2 negative metastatic breast cancer with loss of estrogen and progesterone receptors.

INTRODUCTION: Loss of estrogen receptor (ER) and/or progesterone receptor (PR) might occur during the metastatic progression of ER positive and HER2 negative (ER+/HER2-) breast cancer (BC), but the underpinning molecular alterations remain elusive. We explored the genomic context of HER2- tumors with ER and/or PR loss to investigate potential drivers and actionable alterations that might help personalize treatment of ER+/HER2- BC. METHODS: We accessed data from metastatic HER2- BC included in the MSK-2018 dataset to compare outcome, tumor characteristics and genomic alterations of BC with loss of ER (ER+/-, n = 66) to those maintaining ER positivity (ER+/+, n = 364) or ER negativity (ER-/-, n = 50). We also compared metastatic ER+/+ BC with loss of PR (PR+/-, n = 111) to those maintaining PR positivity (PR+/+, n = 192) or PR negativity (PR-/-, n = 41). RESULTS: In line with previous reports, ER+/- BC was associated with aggressive clinico-pathological characteristics and poor outcome. ER+/- BC showed significantly higher frequency of TP53 and RB1 mutations and lower frequency of PIK3CA and GATA3 mutations compared to ER+/+. ER+/- or PR+/- status was mutually exclusive with ESR1 mutations and was associated with a significantly higher tumor mutational burden. Moreover, ER+/- BC were enriched in driver alterations in the genes of the Notch and Retinoblastoma pathways and showed a significantly lower frequency of level 1 actionable alterations according to OncoKB. CONCLUSIONS: Loss of ER and/or PR may identify a distinct evolutionary trajectory of ER+/HER2- metastatic progression, largely non-overlapping with ESR1-mutant endocrine resistance. Further studies on matched primary and metastatic samples are warranted.

Humans↗
PubMed2025

Clinical and molecular landscape of metastatic extramammary Paget's disease.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignancy without established systemic therapy. EMPD shares molecular features with breast cancer, such as human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression, but their clinical relevance remains unclear. MATERIALS AND METHODS: Tumors from 20 metastatic invasive EMPD cases were analyzed for molecular and biological features. Genomic features, transcriptomic profiles, and HER2 and HR expression status were investigated using immunohistochemistry, fluorescence in situ hybridization, and targeted-genome next-generation sequencing and nCounter BC360 panels. Metastatic breast cancer samples were used as a comparison to clarify metastatic EMPD's clinical relevance. RESULTS: Estrogen receptor expression was observed in 45% of EMPD tumors, while only 10% expressed progesterone receptor. HER2 was overexpressed in 30% of cases, and HER2-directed therapies were durably effective. Among 8 patients with NGS data, 63% (5/8) harbored oncogenic ERBB2 alterations independent of HER2 expression. BC360 profiling revealed biological differences between EMPD and breast cancer, particularly poor biological compatibility for HR-positive tumors. Immune profiling showed that a subset of EMPD tumors exhibited CD8+ T-cell signatures and PD-1/PD-L1 gene expression comparable to triple-negative breast cancer. The median overall survival was 22.1 months (95% CI, 12.0-42.2), with 16 patients (80%) treated with systemic therapy, including anti-HER2 therapy, hormonal therapy, or cytotoxic therapies based on their molecular features. CONCLUSIONS: This study highlights the unique molecular and biological features of metastatic EMPD, emphasizing the need for tailored treatment approaches. This information should be used to guide future clinical strategies for metastatic EMPD.

Humans↗
PubMed2024

Molecular analysis of primary and metastatic sites in patients with renal cell carcinoma.

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Humans↗
PubMed1978

Role of vascular proliferation on angiographic appearance and encapsulation of experimental traumatic and metastatic brain abscesses.

Experimental traumatic abscesses were produced in rhesus monkeys by intracerebral injection of nutrient agar contaminated with Staphylococcus epidermidis, and metastatic abscesses were induced by intracarotid embolization of silicone cylinders contaminated with Staphylococcus epidermidis. All monkeys underwent preoperative and serial postoperative carotid angiography. Traumatic abscesses produced early capsular blushes and progressive anterior cerebral artery displacements. Metastatic abscesses induced transient midline shifts but no capsular stains. Postmortem studies on the monkeys showed that mean capsular thickness and segmental wall vascularity of the traumatic and metastatic abscesses were significantly different (p less than 0.001), despite equal abscess ages and similar abscess volumes. In comparison to traumatic abscesses, metastatic abscesses demonstrated reduced inflammatory cell infiltration and retarded collagen formation around proliferating capsular vessels. Brain surrounding the metastatic abscesses demonstrated ischemic changes. The results suggest that 1) capsular blushes during cerebral angiography are secondary to vascular proliferation within the capsule and not to compression of surrounding brain, 2) vascular staining reflects capsular thickness, 3) capsular vascularity contributes to collagen formation, 4) encapsulation is dependent upon the integrity of surrounding brain, and 5) adjacent cerebral ischemia may impede inflammatory responses involved in capsule formation.

Animals↗