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At least 19 recordsLinked to original sources
PubMed2020

Genomic Analysis of Circulating Tumor Cells at the Single-Cell Level.

Circulating tumor cells (CTCs) have a great potential for noninvasive diagnosis and real-time monitoring of cancer. A comprehensive evaluation of four whole genome amplification (WGA)/next-generation sequencing workflows for genomic analysis of single CTCs, including PCR-based (GenomePlex and Ampli1), multiple displacement amplification (Repli-g), and hybrid PCR- and multiple displacement amplification-based [multiple annealing and loop-based amplification cycling (MALBAC)] is reported herein. To demonstrate clinical utilities, copy number variations (CNVs) in single CTCs isolated from four patients with squamous non-small-cell lung cancer were profiled. Results indicate that MALBAC and Repli-g WGA have significantly broader genomic coverage compared with GenomePlex and Ampli1. Furthermore, MALBAC coupled with low-pass whole genome sequencing has better coverage breadth, uniformity, and reproducibility and is superior to Repli-g for genome-wide CNV profiling and detecting focal oncogenic amplifications. For mutation analysis, none of the WGA methods were found to achieve sufficient sensitivity and specificity by whole exome sequencing. Finally, profiling of single CTCs from patients with non-small-cell lung cancer revealed potentially clinically relevant CNVs. In conclusion, MALBAC WGA coupled with low-pass whole genome sequencing is a robust workflow for genome-wide CNV profiling at single-cell level and has great potential to be applied in clinical investigations. Nevertheless, data suggest that none of the evaluated single-cell sequencing workflows can reach sufficient sensitivity or specificity for mutation detection required for clinical applications.

Carcinoma, Non-Small-Cell Lung↗
PubMed2014

Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow.

BACKGROUND: Therapeutic decisions in cancer are generally guided by molecular biomarkers or, for some newer therapeutics, primary tumor genotype. However, because biomarkers or genotypes may change as new metastases emerge, circulating tumor cells (CTCs) from blood are being investigated for a role in guiding real-time drug selection during disease progression, expecting that CTCs will comprehensively represent the full spectrum of genomic changes in metastases. However, information is limited regarding mutational heterogeneity among CTCs and metastases in breast cancer as discerned by single cell analysis. The presence of disseminated tumor cells (DTCs) in bone marrow also carry prognostic significance in breast cancer, but with variability between CTC and DTC detection. Here we analyze a series of single tumor cells, CTCs, and DTCs for PIK3CA mutations and report CTC and corresponding metastatic genotypes. METHODS: We used the MagSweeper, an immunomagnetic separation device, to capture live single tumor cells from breast cancer patients' primary and metastatic tissues, blood, and bone marrow. Single cells were screened for mutations in exons 9 and 20 of the PIK3CA gene. Captured DTCs grown in cell culture were also sequenced for PIK3CA mutations. RESULTS: Among 242 individual tumor cells isolated from 17 patients and tested for mutations, 48 mutated tumor cells were identified in three patients. Single cell analyses revealed mutational heterogeneity among CTCs and tumor cells in tissues. In a patient followed serially, there was mutational discordance between CTCs, DTCs, and metastases, and among CTCs isolated at different time points. DTCs from this patient propagated in vitro contained a PIK3CA mutation, which was maintained despite morphological changes during 21 days of cell culture. CONCLUSIONS: Single cell analysis of CTCs can demonstrate genotypic heterogeneity, changes over time, and discordance from DTCs and distant metastases. We present a cautionary case showing that CTCs from any single blood draw do not always reflect metastatic genotype, and that CTC and DTC analyses may provide independent clinical information. Isolated DTCs remain viable and can be propagated in culture while maintaining their original mutational status, potentially serving as a future resource for investigating new drug therapies.

Bone Marrow↗
PubMed2026

Establishment of a multi-targeted magnetic combined enrichment system for circulating tumor cells in gastric cancer and analysis of their genomic profiles.

Background: This study aims to establish an efficient Circulating tumor cells (CTCs) multi-targeted magnetic combined sorting system for Gastric cancer (GC), while comparing it with tissue and circulating tumor DNA (ctDNA) samples to evaluate its feasibility and consistency for genomic profiling analysis. Method: Establish an efficient CTCs sorting system for GC targeting epithelial cell adhesion molecule, cell surface vimentin, and protein tyrosine kinase 7, and evaluate its physicochemical properties and cell capture efficiency. Assess the feasibility of tumor cell detection through animal experiments. Sixty-eight GC patients underwent CTCs detection. Clinical information was analyzed to evaluate the clinical utility of CTCs in the auxiliary diagnosis of GC. Next-generation sequencing was performed on GC tissue, CTCs, and ctDNA samples to assess the consistency of genetic mutations across different sample types. Results: The constructed CTCs sorting system exhibits excellent physicochemical properties, achieving a capture rate of 94.68%. Animal studies confirm a positive correlation between tumor cells count and tumor volume. The number of CTCs in the blood of GC patients is significantly correlated with tumor size, stage, and metastasis. The CTCs count in GC patients is significantly higher than in healthy individuals and high-risk groups for cancer, with diagnostic sensitivity and specificity of 97.29% and 97.73%, respectively. The mutation detection rate in CTCs samples was significantly higher than that in tissue and ctDNA samples. The concordance rate between CTCs and tissue mutations was 24.32%, while the concordance rate between CTCs and ctDNA mutations was 19.05%. Conclusion: This study successfully established a multi-target combined CTCs multi-targeted magnetic combined sorting system for GC. CTCs detection based on this system can be used for the auxiliary diagnosis of GC patients. Furthermore, compared to GC tissue and ctDNA samples, CTCs detection enables more comprehensive genomic profiling analysis and serves as an important supplement to GC genomic analysis.

Humans↗
PubMed1992

NK cell activity in treated prostate cancer patients as a probe for circulating tumor cells: hormone regulatory effects in vivo.

Natural killer (NK) cell activity was studied together with tumor marker serotests (PSA, PAP) and blood testosterone, estradiol, cortisol, and prolactin concentrations in treated prostate cancer patients. NK cell activity data were correlated with tumor stage (stage D0 + D1 versus stage D2) and showed statistically insignificant differences. Both tumor progression and stabilization of metastatic disease, triggered by the application of more appropriate therapy in progressive subjects, yielded low NK activity data. By contrast, normal NK activity was found during both partial remission of stage D2 tumor and stabilization of the same disease, after an initial period of tumor remission. Differences between NK activity data from the aforementioned two groups are statistically significant (P less than 0.01). In subjects examined, the application of NK activity assay to those with advanced disease reflected changes in the outcome of the treatment more closely than it did routine tumor marker assessment. The activity of NK cells seems unaffected by changes in basal blood estradiol, cortisol, testosterone, and prolactin concentrations that occur during therapy with pharmacological agents (estradiol, cyproterone acetate, diethylstilbestrol, and flutamide) and during surgical castration. The reported NK activity recordings in treated prostate cancer patients might be indicative of the presence of tumor cells in the circulation. If this holds true, the measurement of NK activity would appear to furnish urological oncology with a new tool for early, rapid recognition of progressive metastatic tumors.

Acid Phosphatase↗
PubMed1976

Bioassay for quantitating circulating tumor cells in a syngeneic mouse tumor system.

A bioassay is described for the quantitation of tumor cells in blood specimens in a syngeneic mouse tumor system (Sarcoma 1 in A/J mice). The procedure involved i.m. injection of blood containing tumor cells into each thigh of normal recipient mice and, 14 days later, examination of the sites of injection for evidence of tumor growth. For each specimen, a tumor index was calculated based on the number of tumor takes and the size of the tumors. The number of tumor cells was determined by comparison with tumor indices from standard specimens with known number of tumor cells. Optimal conditions for this assay were investigated. We have used this bioassay to quantitate tumor cells in the venous blood of tumor-bearing animals under various treatments and manipulations. At the same time, the incidence of regional node metastasis was obtained by direct histological examination. Surgical removal of a well-established primary tumor enhanced the dissemination of the tumor, as evidenced by an increased incidence in regional node metastasis and an increase in the number of tumor cells reaching the venous circulation. Similar results were obtained when the tumor-bearing feet were ligated to produce ischemia of the primary tumor. Repeated physical trauma to the primary tumor resulted in increased dissemination of tumor cells into the venous circulation, but it did not increase the incidence of regional node metastasis. Immunosuppression of the tumor-bearing animals increased the dissemination of tumor cells, whereas immunostimulation decreased the dissemination.

Animals↗
PubMed1976

The role of immune factors in the survival of circulating tumor cells.

The effects of immune serum on the survival of hematogenously disseminated malignant cells were investigated in six murine tumor systems with varying immunogenicity. Blood containing circulating tumor cells demonstrable by bioassay was obtained from donor mice with disseminated tumor. The cellular fraction was isolated by centrifugation and resuspended in immune serum obtained from donor animals bearing the same tumor (Group 1), in immune serum from mice bearing a differing tumor (Group 2), or in normal nonimmune serum (Group 3). The mixed cellular and serum fractions were intravenously inoculated into normal recipient mice which were subsequently scored for the development of pulmonary tumors. Similar incidence (35-50%) of pulmonary tumor deposits were seen in Groups 2 and 3. A significant enhancement in the incidence of lung tumors was present in the Group 1 animals for all tumor systems studies. It was suggested that the observed enhancement resulted from factors present in isologous immune serum but absent from both normal serum and immune serum obtained from hosts bearing heterologous tumors.

Adenocarcinoma↗
PubMed2026

Circulating tumor cells identify a disseminated genomic high-risk phenotype within IMS-IMWG 2025 staging in newly diagnosed multiple myeloma.

The 2025 IMS-IMWG consensus genomic staging (CGS) system has improved genomic risk stratification in newly diagnosed multiple myeloma (NDMM), yet does not capture whether high-risk clones have acquired a disseminated phenotype. We investigated whether circulating tumor cells (CTC) refine CGS and enable longitudinal residual disease monitoring. We retrospectively analyzed 631 MM patients from the NICHE cohort (NCT04645199) who underwent CTC assessment across disease phases. Among 410 patients assessed at diagnosis, CTC were detectable in 63.9% and correlated with both bone marrow plasma cell infiltration and accumulation of high-risk cytogenetic abnormalities. In 359 NDMM patients with adequate follow-up, a cohort-derived CTC threshold of 0.38% independently predicted inferior progression-free survival (PFS) after multivariable adjustment. Importantly, CTC refined prognostic stratification specifically within the CGS high-risk subgroup. Patients with CGS high-risk/CTC-high disease had the shortest PFS, thereby defining a disseminated genomic high-risk phenotype comprising 12.4% (39/314) of evaluable NDMM patients. In follow-up cohorts, detectable CTC were associated with inferior outcomes in 127 patients assessed during non-progressive disease states, whereas combined CTC and bone marrow minimal residual disease assessment stratified outcomes in 120 patients with paired measurements. Overall, CTC-integrated CGS supports minimally invasive baseline risk stratification and longitudinal disease monitoring.

Journal Article↗
PubMed1977

Circulating tumor cells in murine myeloma.

BALB/c mice bearing subcutaneous ADJ-PC5 myelomas had hematologic findings suggestive of a preleukemic syndrome: thrombocytopenia, anemia, leukocytosis, and megakaryocytic hyperplasia. Six BALB/c myelomas were successfully transplanted sc by fragments or cell suspensions of spleens from mice bearing a subcutaneous tumor, though typical myeloma cells were difficult to visualize by light microscopy in these spleens. The fidelity of transmission of the ADJ-PC5 myeloma by this procedure was shown by the retention of idiotypic specificity of the immunoglobulin produced by the tumor in a radioimmunoassay. The tumorigenic cell that homed to the spleen was apparent as early as 8 days after sc transplantation of the myeloma. The spleens of tumor-bearing mice, however, could destroy or suppress the expansion or growth of a limited number of cells that had migrated to the spleens. Tumorigenic cells present in the peripheral circulation constituted 2-3% of the leukocytes. These cells, however, had reduced levels of the murine myeloma viral and cell-associated antigens, were difficult to detect by an indirect immunofluorescence assay, and did not rapidly divide in this environment, as indicated by the very low number of cells detected by autoradiography.

Animals↗
PubMed1977

Detection of soluble tumor-associated antigens in serum of tumor-bearing rats and their immunological role in vivo.

Circulating soluble tumor antigens were detected in the serum of tumor-bearing rats. Sublethally irradiated W/Fu rats inoculated with syngeneic C58(NT)D Gross virus-induced lymphoma served as the source of tumor antigens. Soluble antigens were assessed by specific inhibition of the complement-mediated cytotoxicity of isogenic W/Fu anti-C58(NT)D antibodies against 51Cr tumor target cells. With a s.c. inoculum of 5 X 10(7) tumor cells, circulating tumor antigens were first detected at Day 8, and a maximum concentration was reached by Day 13 to 14, which coincided with the peak of tumor growth and was followed by the sudden death of the animals. Pooled serum from tumor-bearing rats was fractioned on Sephadex G-150 and resulted in one peak that contained all of the antigenic activity. The molecular weight of this fraction was estimated to be 50,000 to 60,000 daltons. Presensitization of normal rats with soluble tumor antigens resulted in a specific acceleration of tumor growth and delay in tumor rejection. Specificity was shown by lack of C58(NT)D tumor enhancement in rats presensitized with serum containing tumor antigens from a syngeneic but antigenically unrelated WR-6 lymphoma. The biological significance of circulating soluble tumor antigen mediating specific immunosuppression against an immunogenic tumor is discussed.

AKR murine leukemia virus↗
PubMed1979

Quantitative study on the liberation of tumor cells into the circulating blood.

A study was undertaken to investigate the mechanism of liberation of tumor cells into the blood stream in connection with the process of tumor growth, using three strains of ascites tumor such as Yoshida sarcoma (YS) with infiltrative growth pattern, AH100B with expansive one, and AH109A with intermediate one. For this experiment, a new method for the quantitation of the number of circulating tumor cells was devised. From its results, it was concluded as follows: (1) Tumor cells appear first in the circulating blood at the transitional phase from logarithmic growth to declining growth. (2) Tumor size is a macroscopical index of the risk of the liberation of tumor cells into the blood stream. (3) Tumor necrosis is a histological sign suggesting that the tumor growth phase is declining, namely, that hematogenous dissemination of tumor cells has begun already. (4) There is a striking difference in the frequency and number of tumor cells in the venous blood among these three tumor strains. The tumour strains in order of the number of the circulating tumor cells are YS, AH109A, and AH100B. (5) In YS and AH109A, the transition of the number of tumor cells liberated into the blood stream is closely related to the growth process of tumor tissue. (6) Liberated cells of AH109A and AH100B disappear promptly from the blood stream.

Animals↗
PubMed1979

[Walker's 256 carcinosarcoma: metastatic dissemination in two cell lines (author's transl)].

Walker's 256 carcinosarcoma a transplantable tumor of the rate changes its behaviour as a consequence of various factors. In this paper we compare the evolution of 2 lines of the tumor: WM 16 (muscular) and Christ Hospital (ascitic) both inoculated intramuscularly. Animals receiving line WM 16 had a severe rapidly progressive evolution dying around day 14 after inoculation with diffuse metastases to lymph nodes (65% of animals), kidneys (53%), spleen (50%), lungs (46.5%), liver (45%), bone marrow (44.8%), in 56% of the animals there were circulating tumoral cells. Animals receiving Christ Hospital line survived up to 40 days, metastases were limited do lungs (48.7%) and lymph nodes (31.7%) and only in 2 of 45 animals circulating tumoral cells were observed.

Animals↗
PubMed1992

Detection and quantitation of malignant cells in the peripheral blood of multiple myeloma patients.

One of the distinguishing features of multiple myeloma (MM) is the proliferation of plasma cells that home to the bone marrow (BM). However, there still remains some uncertainty concerning the presence of related malignant cells in the peripheral blood of myeloma patients. Using consensus oligonucleotide primers, we amplified the third complementary determining region (CDR3) of rearranged immunoglobulin heavy chain alleles from MM marrow samples by polymerase chain reaction (PCR). From the sequences of the products, we derived allele-specific oligonucleotides (ASO), and these were used in subsequent amplification reactions to detect malignant clones in the peripheral blood of myeloma patients. This method is highly specific and sensitive to 1 malignant cell in the background of 10(5) normal cells. Using this method we detected circulating malignant cells in 13 of 14 previously untreated MM patients. Furthermore, by applying ASO-PCR to artificial titrations of initial BM DNA sample into normal peripheral blood lymphocyte (PBL) DNA we were able to generate standard curves and quantitate the amount of tumor in the patient PBL. We observed a wide variation in the amount of circulating tumor between patients. In addition, we found that the incidence of circulating tumor cells was independent of BM tumor burden and stage of disease. The detection and quantitation of circulating tumor cells in the PBL of MM patients may offer an alternative assessment of the disease and may be an important consideration in the use of peripheral stem cells in bone marrow transplantation.

Base Sequence↗
PubMed1978

Transitional cell carcinoma: circulating tumor antigen correlated with presence/absence of tumor (leukocyte migration assay).

Sera from patients with TCC of the urinary bladder have been fractionated. We tested the fractions for activity in the leukocyte migration test, using peripheral blood leukocytes from TCC patients, other cancer patients, and healthy control donors as indicator cells. The results suggest that an antigen associated with TCC can be detected in the sera of patients bearing TCC but not in tumor-free individuals.

Antigens, Neoplasm↗
PubMed2025

Mismatch-introduced crRNA guided PCR-CRISPR/Cas12a platform improves EGFR point mutation detection in single tumor cell.

Dynamic monitoring of epidermal growth factor receptor (EGFR) mutations is essential for the early identification of resistance and treatment adaptation. Single-cell heterogeneity analysis is crucial for precision cancer medicine, yet sensitive and specific detection methods for individual tumor cells remain challenging. Here, we develop a PCR-CRISPR/Cas12a platform enhanced by the incorporation of mismatched base in crRNA at specific site for single-cell point mutation detection. This platform demonstrated high specificity and sensitivity, detecting point mutation at a frequency of 0.1% and in as low as 1.02 ng of genomic DNA, which represents an improvement over the amplification-refractory mutation system PCR (ARMS-PCR). Notably, the accuracy of the platform is highly consistent with next-generation sequencing (NGS), as evidenced by Kappa test values surpassing 0.9. By utilizing a conical-pore membrane with optimized porosity for single circulating tumor cell (CTC) enrichment, our platform enables point mutations detection in individual tumor cells, offering potential enhancements in precision and reliability for EGFR mutation analysis. This novel methodology holds potential for more accurate and personalized cancer treatment strategies.

Humans↗
PubMed2026

Baseline Plasma Cell-Free and Circulating Tumor DNA Across Lymphoma Subtypes and Its Prognostic Impact in Diffuse Large B-Cell Lymphoma.

BACKGROUND: Circulating tumor DNA (ctDNA) analysis enables real‑time assessment of the tumor burden and genomic complexity in lymphomas. However, real‑world evidence across lymphoma subtypes is limited. METHODS: We analyzed cell‑free DNA (cfDNA) and ctDNA data from 336 consecutive patients with newly diagnosed Hodgkin or non-Hodgkin lymphoma in 2022 and evaluated their prognostic impact in diffuse large B‑cell lymphoma (DLBCL). RESULTS: We detected somatic alterations in 248 of 336 patients (73.8%). DLBCL and follicular lymphoma showed the highest variant prevalences and ctDNA burdens. Epigenetic regulators, including KMT2D, CREBBP, TET2, and HIST1H1E, constituted the dominant class of genes with recurrent alterations. Plasma variant profiles closely mirrored publicly available, tissue‑based next-generation sequencing datasets. The baseline ctDNA burden correlated with adverse clinical features, and ctDNA positivity was associated with failure to achieve complete remission. In DLBCL, elevated cfDNA (top quartile) and a high International Prognostic Index (IPI) were independently associated with shorter overall and progression‑free survival. However, the total variant count per patient was not significantly associated with survival after adjustment. CONCLUSIONS: Baseline plasma cfDNA and ctDNA assessments are feasible in routine practice and recapitulate tissue-variant landscapes. Elevated cfDNA concentrations-but not the total variant count-were independently associated with survival in DLBCL, providing prognostic information beyond the IPI and supporting integration of plasma-based biomarkers into multiparameter risk models. Gene‑level ctDNA associations should be regarded as exploratory and hypothesis‑generating.

Cell-free DNA↗