scholarly journals Emerging paradigms in metastasis research

2020 ◽  
Vol 218 (1) ◽  
Author(s):  
Ashik Ahmed Abdul Pari ◽  
Mahak Singhal ◽  
Hellmut G. Augustin
Keyword(s):  
Metastatic Disease ◽  
Primary Tumor ◽  
Holistic Approach ◽  
Primary Tumors ◽  
Metastatic Colonization ◽  
Discovery Research ◽  
Metastasis Research ◽  
Recent Developments ◽  
Rate Limiting ◽  
Therapeutic Avenue

Historically, therapy of metastatic disease has essentially been limited to using strategies that were identified and established to shrink primary tumors. The limited efficacy of such treatments on overall patient survival stems from diverging intrinsic and extrinsic characteristics of a primary tumor and metastases originating therefrom. To develop better therapeutic strategies to treat metastatic disease, there is an urgent need to shift the paradigm in preclinical metastasis research by conceptualizing metastatic dissemination, colonization, and growth as spatiotemporally dynamic processes and identifying rate-limiting vulnerabilities of the metastatic cascade. Clinically, while metastatic colonization remains the most attractive therapeutic avenue, comprehensive understanding of earlier steps may unravel novel metastasis-restricting therapies for presurgical neoadjuvant application. Moving beyond a primary tumor-centric view, this review adopts a holistic approach to understanding the spatial and temporal progression of metastasis. After reviewing recent developments in metastasis research, we highlight some of the grand challenges and propose a framework to expedite mechanism-based discovery research feeding the translational pipeline.

scholarly journals In Vivo Lymphatic Circulating Tumor Cells and Progression of Metastatic Disease

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2866
Author(s):  
Mikyung Han ◽  
Julia Alex Watts ◽  
Azemat Jamshidi-Parsian ◽  
Urooba Nadeem ◽  
Mustafa Sarimollaoglu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
High Sensitivity ◽  
Disease Stage ◽  
Primary Tumors ◽  
Integrative Assessment

The dissemination of circulating tumor cells (CTCs) by lymph fluid is one of the key events in the development of tumor metastasis. However, little progress has been made in studying lymphatic CTCs (L-CTCs). Here, we demonstrate the detection of L-CTCs in preclinical mouse models of melanoma and breast cancer using in vivo high-sensitivity photoacoustic and fluorescent flow cytometry. We discovered that L-CTCs are be detected in pre-metastatic disease stage. The smallest primary tumor that shed L-CTCs was measured as 0.094mm×0.094mm, its volume was calculated as 0.0004 mm3; and its productivity was estimated as 1 L-CTC per 30 minutes. As the disease progressed, primary tumors continued releasing L-CTCs with certain individual dynamics. The integrated assessment of lymph and blood underlined the parallel dissemination of CTCs at all disease stages. However, the analysis of links between L-CTC counts, blood CTC (B-CTC) counts, primary tumor size and metastasis did not reveal statistically significant correlations, likely due to L-CTC heterogeneity. Altogether, our results showed the feasibility of our diagnostic platform using photoacoustic flow cytometry for preclinical L-CTC research with translational potential. Our findings also demonstrated new insights into lymphatic system involvement in CTC dissemination. They help to lay the scientific foundation for the consideration of L-CTCs as prognostic markers of metastasis and to emphasize the integrative assessment of lymph and blood.

scholarly journals Metastatic Pheochromocytoma/Paraganglioma Related to Primary Tumor Development in Childhood or Adolescence: Significant Link to SDHB Mutations

2011 ◽  
Vol 29 (31) ◽  
pp. 4137-4142 ◽  
Author(s):  
Kathryn S. King ◽  
Tamara Prodanov ◽  
Vitaly Kantorovich ◽  
Tito Fojo ◽  
Jacqueline K. Hewitt ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
Tumor Development ◽  
Gene Mutations ◽  
National Institutes Of Health ◽  
High Rate ◽  
Adrenal Tumors ◽  
Primary Tumors ◽  
Tumor In Childhood

Purpose To present data on the high rate of SDHB mutations in patients with metastatic pheochromocytoma/paraganglioma whose initial tumor presentation began in childhood or adolescence. Patients and Methods From 2000 to 2010, 263 patients with pheochromocytoma/paraganglioma were evaluated through the National Institutes of Health (NIH), Bethesda, MD. Of the 263 patients, 125 patients were found to have metastatic disease; of these 125 patients, 32 patients presented with a tumor before 20 years of age. An additional 17 patients presented with a tumor before 20 years of age but demonstrated no development of metastatic disease. Genetic testing for mutations in the VHL, MEN, and SDHB/C/D genes was performed on patients without previously identified genetic mutations. Results Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA showed SDHB mutations in 23 patients (71.9%), SDHD mutations in three patients (9.4%), VHL mutations in two patients (6.3%), and an absence of a known mutation in four patients (12.5%). The majority of these 32 patients (78.1%) presented with primary tumors in an extra-adrenal location. Conclusion The majority of patients with metastatic pheochromocytoma/paraganglioma who presented with a primary tumor in childhood/adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommend that patients who present with metastatic pheochromocytoma/paraganglioma with primary tumor development in childhood or adolescence undergo SDHB genetic testing before they undergo testing for other gene mutations, unless clinical presentation or family history suggests a different mutation.

scholarly journals The Treatment and Outcome of Patients With Soft Tissue Sarcomas and Synchronous Metastases

Sarcoma ◽  
2002 ◽  
Vol 6 (2) ◽  
pp. 69-73 ◽  
Author(s):  
John M. Kane ◽  
J. William Finley ◽  
Deborah Driscoll ◽  
William G. Kraybill ◽  
John F. Gibbs
Keyword(s):  
Overall Survival ◽  
Soft Tissue ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
Strong Association ◽  
Soft Tissue Sarcomas ◽  
Poor Overall Survival ◽  
Primary Tumors ◽  
Synchronous Metastases ◽  
Metastatic Sites

Introduction: There is a strong association between poor overall survival and a short disease-free interval for patients with soft tissue sarcomas (STS) and metastatic disease. Patients with STS and synchronous metastases should have a very dismal prognosis.The role of surgery in this subgroup of patients with STS has not been defined.Patients and Methods: A single-institution retrospective review was performed of 48 patients with STS and synchronous metastases in regard to patient demographics, presentation, tumor characteristics, metastatic sites, treatment, follow-up, and survival over a 27-year period.Results: Most primary tumors were ≥10 cm (58%), high-grade histology (77%), and located on the extremity (60%).The most frequent site of metastatic disease was the lung (63%); 27% of patients had metastases to ≥2 organ sites. Surgery to the primary tumor was performed in 94% of patients (n = 45) and 68% had additional radiation therapy (n = 32). Thirty- five percent of patients underwent at least one metastastectomy (n = 17). Chemotherapy was administered to 90% of patients (n = 43); 31% received ≥3 different regimens (n = 15) and 25% were given intra-arterial or intracavitary therapy (n = 12). Median overall survival was 15 months with a 21% 2-year survival. Local control of the primary tumor was achieved in 54% (n = 26), and metastastectomy was performed in 35% (n = 17). No analyzed factors were associated with an improvement in overall survivalConclusions: Despite multiple poor prognostic factors, the survival of patients with STS and metastases is comparable to those who develop delayed metastatic disease. However, unlike patients who present with metachronous disease, there was no improved survival observed for patients treated with metastastectomy. Consequently, treatment for patients with STS and synchronous metastases should be approached with caution. Surgical management of STS with synchronous metastases must be considered palliative and should be reserved for patients requiring palliation of symptoms. Patients must also be well informed of the noncurative nature of the procedure.

scholarly journals A Requirement for p120-catenin in the metastasis of invasive ductal breast cancer

2020 ◽  
pp. jcs.250639
Author(s):  
Sarah J. Kurley ◽  
Verena Tischler ◽  
Brian Bierie ◽  
Sergey V. Novitskiy ◽  
Aurelia Noske ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Primary Tumor ◽  
Distant Metastases ◽  
Positive Role ◽  
P120 Catenin ◽  
Primary Tumors ◽  
Invasive Ductal Breast Cancer ◽  
Metastatic Colonization ◽  
Metastatic Sites

We have examined the effects of targeted p120 KO in a PyMT mouse model of invasive ductal (mammary) cancer (IDC). Mosaic p120 ablation had little effect on primary tumor growth but caused significant pro-metastatic alterations in the tumor microenvironment leading ultimately to a marked increase in the number and size of pulmonary metastases. Surprisingly, although early effects of p120-ablation included decreased cell-cell adhesion and increased invasiveness, cells lacking p120 were almost entirely unable to colonized distant metastatic sites in vivo. The relevance of this observation to human IDC was established by analysis of a large clinical dataset of 1126 IDCs. As reported by others, p120 downregulation in primary IDC predicted worse overall survival. However, as in the mice, distant metastases were almost invariably p120 positive, even in matched cases where the primary tumors were p120 negative. Collectively, our results demonstrate a strong positive role for p120 (and presumably E-cadherin) during metastatic colonization of distant sites. On the other hand, downregulation of p120 in the primary tumor enhanced metastatic dissemination indirectly via pro-metastatic conditioning of the tumor microenvironment.

scholarly journals DNA Methylation in INA, NHLH2, and THBS4 Is Associated with Metastatic Disease in Renal Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 39
Author(s):  
Olga Katzendorn ◽  
Inga Peters ◽  
Natalia Dubrowinskaja ◽  
Joana M. Moog ◽  
Christel Reese ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Classification Model ◽  
Primary Tumors ◽  
Independent Information ◽  
Tumor Tissues ◽  
Bivariate Logistic Regression

The detection of DNA methylation in primary tumor tissues could be relevant for early stratification of aggressive renal cell carcinomas (RCCs) as a basis for future personalized adjuvant therapy. Methylated TCGA KIRC based candidate CpG loci in INA, NHLH2, and THBS4 that are possibly associated with RCC metastasis were evaluated by pyrosequencing in 154 paired normal adjacent and primary tumor tissues, as well as in 202 metastatic tissues. Statistical analysis was carried out by bivariate logistic regression for group comparisons, log rank survival analysis, and unsupervised and supervised analysis for the classification of tumors. Increased methylation of INA, NHLH2, and THBS4 loci were significantly associated with distant metastasis in primary tumors (p < 0.05), tissue-specific hypermethylation in metastatic (p = 7.88 × 10−8, 5.57 × 10−10, 2.06 × 10−7) and tumor tissues (p = 3.72 × 10−24, 3.17 × 10−13, 1.58 × 10−19), and shortened progression free survival in patients (p = 0.03). Combined use of CpG site-specific methylation permits the discrimination of tissues with metastatic disease and reveals a significant contribution of CpG sites in all genes to the statistical classification model. Thus, metastasis in RCC is significantly associated with methylation alterations in INA, NHLH2, and THBS4 loci, providing independent information for the potential early detection of aggressive renal cancers as a rationale for stratifying patients to adjuvant therapies.

scholarly journals The Potential Role of Selected miRNA in Uveal Melanoma Primary Tumors as Early Biomarkers of Disease Progression

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 271 ◽  
Author(s):  
Joanna Patrycja Wróblewska ◽  
Michał Stefan Lach ◽  
Adam Ustaszewski ◽  
Katarzyna Kulcenty ◽  
Matthew Ibbs ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Primary Tumors ◽  
Oncogenic Pathways ◽  
Micro Rnas ◽  
Mirna Expression Data ◽  
Metastatic Risk

Uveal melanoma (UM) is the most common primary tumor of the eye diagnosed in adults, associated with a high risk of metastasis and thereby, poor prognosis. Among known risk factors for the development of metastatic disease is the loss of BAP1 expression and chromosome 3 monosomy in the primary tumor. However, the expression levels of specific micro RNAs (miRNA) in tumor tissue may also serve as a valuable marker for determining the risk of metastatic disease in patients with primary uveal melanoma. In our study, we analyzed the miRNA expression data of cases selected from The Cancer Genome Atlas study on uveal melanoma, and determined a panel of 15 miRNAs differentially expressed between patients with primary and metastatic disease. Next, 6 miRNAs were validated on a group of 46 tumor samples from primary and metastatic patients. We have shown, that expression of hsa-miR-592, hsa-miR-346, and hsa-miR-1247 was significantly increased, while hsa-miR-506 and hsa-miR-513c were decreased in the tumors of patients with metastatic disease. Hsa-miR-196b expression did not differ between the two subgroups, however, we showed significant correlation with BAP1 expression. Moreover, hsa-miR-592 also showed correlation with monosomy 3 tumors. Gene ontology analysis revealed involvement of those miRNAs with cellular processes mediating the metastatic process. Our results showed that miRNAs play an important role in the deregulation of several oncogenic pathways in UM and can, thereby, promote metastatic spread to distant organs. Moreover, differentially expressed miRNAs may be used as an interesting biomarker for the assessment of metastatic risk in uveal melanoma patients.

Expression of CEACAM1 in pulmonary adenocarcinoma cells and their metastases

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17071-17071
Author(s):  
E. Laack ◽  
O. Schult-Kronefeld ◽  
I. Burkholder ◽  
M. Görn ◽  
B. Andritzky ◽  
...  
Keyword(s):  
Lymph Node ◽  
Metastatic Disease ◽  
Lung Tissue ◽  
Primary Tumor ◽  
Distant Metastases ◽  
Pulmonary Adenocarcinoma ◽  
Normal Lung Tissue ◽  
Normal Lung ◽  
Primary Tumors ◽  
Adenocarcinoma Cells

17071 Background: The cell adhesion molecule CEACAM1 is involved in intercellular adhesion and is expressed in a variety of normal human tissues such as mammary gland, colonic mucosa and prostate. In cases of malignant transformation of these tissues a down regulation or loss of CEACAM1 has been shown. In contrary, CEACAM1 is not expressed in normal lung tissue or melanocytes and it has been demonstrated that a expression in these tissues is associated with the development of metastatic disease. The aim of the present investigation was to analyze a possible association between the expression of CEACAM1 in pulmonary adenocarcinoma cells and their lymph node and hematogenous metastatic cells. Methods: CEACAM1 expression was immunhistochemically evaluated in primary tumor cells, cells in lymph nodes and in distant metastases of 96 patients with metastatic adenocarcinoma of the lung who had undergone surgery between 1999 and 2002. Results: An expression of CEACAM1 has been shown in 78 of 96 primary tumors. We found a significant positive correlation between the CEACAM1 expression on the cells of the primary tumor and the lymph node metastases (p<0.005) and the hematogenous metastases (p<0.05). Conclusion: As shown before, CEACAM1 is not expressed in normal lung tissue but in most primary adenocarcinomas of the lung. We are the first to demonstrate, that its expression is preserved in the lymph node and hematogenous metastases in metastatic disease implicating that its expression is of functional significance of both metastatic sites. No significant financial relationships to disclose.

scholarly journals Breast Cancer Cell Re-Dissemination from Lung Metastases—A Mechanism for Enhancing Metastatic Burden

2021 ◽  
Vol 10 (11) ◽  
pp. 2340
Author(s):  
Lucia Borriello ◽  
John Condeelis ◽  
David Entenberg ◽  
Maja H. Oktay
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Metastatic Disease ◽  
Breast Cancer Cells ◽  
Lung Metastases ◽  
Primary Tumors ◽  
Metastatic Burden ◽  
First Time ◽  
Do So

Although metastatic disease is the primary cause of mortality in cancer patients, the mechanisms leading to overwhelming metastatic burden are still incompletely understood. Metastases are the endpoint of a series of multi-step events involving cancer cell intravasation, dissemination to distant organs, and outgrowth to metastatic colonies. Here we show, for the first-time, that breast cancer cells do not solely disseminate to distant organs from primary tumors and metastatic nodules in the lymph nodes, but also do so from lung metastases. Thus, our findings indicate that metastatic dissemination could continue even after the removal of the primary tumor. Provided that the re-disseminated cancer cells initiate growth upon arrival to distant sites, cancer cell re-dissemination from metastatic foci could be one of the crucial mechanisms leading to overt metastases and patient demise. Therefore, the development of new therapeutic strategies to block cancer cell re-dissemination would be crucial to improving survival of patients with metastatic disease.

scholarly journals Machine Learning and Radiomics Applications in Esophageal Cancers Using Non-Invasive Imaging Methods—A Critical Review of Literature

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2469
Author(s):  
Chen-Yi Xie ◽  
Chun-Lap Pang ◽  
Benjamin Chan ◽  
Emily Yuen-Yuen Wong ◽  
Qi Dou ◽  
...  
Keyword(s):  
Machine Learning ◽  
Quantitative Imaging ◽  
Risk Groups ◽  
Review Of Literature ◽  
Primary Tumors ◽  
Non Invasive ◽  
Significant Difference ◽  
Recent Developments ◽  
Health Significance ◽  
Imaging Markers

Esophageal cancer (EC) is of public health significance as one of the leading causes of cancer death worldwide. Accurate staging, treatment planning and prognostication in EC patients are of vital importance. Recent advances in machine learning (ML) techniques demonstrate their potential to provide novel quantitative imaging markers in medical imaging. Radiomics approaches that could quantify medical images into high-dimensional data have been shown to improve the imaging-based classification system in characterizing the heterogeneity of primary tumors and lymph nodes in EC patients. In this review, we aim to provide a comprehensive summary of the evidence of the most recent developments in ML application in imaging pertinent to EC patient care. According to the published results, ML models evaluating treatment response and lymph node metastasis achieve reliable predictions, ranging from acceptable to outstanding in their validation groups. Patients stratified by ML models in different risk groups have a significant or borderline significant difference in survival outcomes. Prospective large multi-center studies are suggested to improve the generalizability of ML techniques with standardized imaging protocols and harmonization between different centers.

scholarly journals Metastatic Esophageal Carcinoma Cells Exhibit Reduced Adhesion Strength and Enhanced Thermogenesis

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1213
Author(s):  
Zihe Huo ◽  
Mariana Sá Santos ◽  
Astrid Drenckhan ◽  
Stefan Holland-Cunz ◽  
Jakob R. Izbicki ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Tumor Cells ◽  
Cell Lines ◽  
Adhesion Strength ◽  
Primary Tumor ◽  
Carcinoma Cell ◽  
Metastatic Potential ◽  
Primary Tumors ◽  
Metastatic Cell ◽  
Carcinoma Cell Lines

Despite continuous improvements in multimodal therapeutic strategies, esophageal carcinoma maintains a high mortality rate. Metastases are a major life-limiting component; however, very little is known about why some tumors have high metastatic potential and others not. In this study, we investigated thermogenic activity and adhesion strength of primary tumor cells and corresponding metastatic cell lines derived from two patients with metastatic adenocarcinoma of the esophagus. We hypothesized that the increased metastatic potential of the metastatic cell lines correlates with higher thermogenic activity and decreased adhesion strength. Our data show that patient-derived metastatic esophageal tumor cells have a higher thermogenic profile as well as a decreased adhesion strength compared to their corresponding primary tumor cells. Using two paired esophageal carcinoma cell lines of primary tumor and lymph nodes makes the data unique. Both higher specific thermogenesis profile and decreased adhesion strength are associated with a higher metastatic potential. They are in congruence with the clinical patient presentation. Understanding these functional, biophysical properties of patient derived esophageal carcinoma cell lines will enable us to gain further insight into the mechanisms of metastatic potential of primary tumors and metastases. Microcalorimetric evaluation will furthermore allow for rapid assessment of new treatment options for primary tumor and metastases aimed at decreasing the metastatic potential.

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