Subsequent Metastasis Research Articles

A transcriptomic signature for prostate cancer relapse prediction identified from the differentially expressed genes between TP53 mutant and wild-type tumors

For prostate cancer (PCa) patients, biochemical recurrence (BCR) is the first sign of disease relapse and the subsequent metastasis. TP53 mutations are relatively prevalent in advanced PCa forms. We aimed to utilize this knowledge to identify robust transcriptomic signatures for BCR prediction in patients with Gleason score ≥ 7 cancers, which cause most PCa deaths. Using the TCGA-PRAD dataset and the novel data-driven stochastic approach proposed in this study, we identified a 25-gene signature from the genes whose expression in tumors was associated with TP53 mutation statuses. The predictive strength of the signature was assessed by AUC and Fisher’s exact test p-value according to the output of support vector machine-based cross validation. For the TCGA-PRAD dataset, the AUC and p-value were 0.837 and 5 × 10–13, respectively. For five external datasets, the AUCs and p-values ranged from 0.632 to 0.794 and 6 × 10–2 to 5 × 10–5, respectively. The signature also performed well in predicting relapse-free survival (RFS). The signature-based transcriptomic risk scores (TRS) explained 28.2% of variation in RFS on average. The combination of TRS and clinicopathologic prognostic factors explained 23–72% of variation in RFS, with a median of 54.5%. Our method and findings are useful for developing new prognostic tools in PCa and other cancers.

Abstract 265: Inhibiting proteasome in extracellular matrix (ECM) detached cells promotes anoikis

Abstract The underlying mediators for altered cell-extracellular matrix (ECM) communication in tumors remain to be understood and are likely to be multifactorial. Detached cells from the ECM are often cleared by a death process called ‘anoikis’. Anoikis is critical for health and homeostasis maintenance. However, aggressive cancer cells acquire anoikis resistance to promote invasion and metastasis in new sites. We previously identified metabolic reprogramming and upregulation of Vacuolar-ATPase members responsible for anoikis resistance while the manipulation of these pathways induced anoikis. However, the mechanisms underlying anoikis resistance and subsequent metastasis are yet to be fully elucidated, thus limiting anoikis-targeting drug exploration for metastasis control. Herein, our RNA-seq data revealed upregulated genes associated with proteasome activity (such as PSMA, PSMB, PSMD, and POMP) in ECM detached cancer cells compared to adherent cancer cells. Targeting this, using proteasome inhibitors (MG132 or bortezomib) in breast cancer, cervical, and melanoma cell lines sensitized cancer cells to anoikis through increased cellular, mitochondrial stress, and misfolded protein accumulation. Moreover, Bortezomib treatment in vivo in melanoma tumor model repressed metastasis. These data demonstrate proteasome activity is hijacked by ECM detached cancer cells to maintain proteostasis thus promoting anoikis resistance and metastasis. Regardless of the impressive outcome in treating hematological malignancies, proteasome inhibitors show little effect against solid tumors in several clinical trials that utilized selective and more potent inhibitors either as a single or in combinatory therapy. In this sense, our finding suggests proteasome inhibitors may be more attractive for metastasis control rather than local tumor treatment. Altogether, our findings demonstrate enhanced proteasome activity within the tumor cells is critical for anoikis resistance, and targeting this can markedly overcome resistance and control tumor metastasis. Citation Format: Funmilayo Adeshakin, Guizhong Zhang, Adeleye Adeshakin, Xiaochun Wan. Inhibiting proteasome in extracellular matrix (ECM) detached cells promotes anoikis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 265.

Gastroesophageal Glomus Tumors: Clinicopathologic and Molecular Genetic Analysis of 26 Cases With a Proposal for Malignancy Criteria.

Although criteria for malignancy have been established for glomus tumors of soft tissue, there are no accepted criteria for gastroesophageal glomus tumors, the behavior of which is considered to be unpredictable. Recently, both benign and aggressive gastroesophageal glomus tumors have been shown to harbor CARMN :: NOTCH2 fusions, but, as yet, there are no described genetic features that predict clinical behavior. Here, we evaluated 26 gastroesophageal glomus tumors to investigate histologic and genetic features that might predict malignant behavior. Seventeen patients (65%) were male. The median age at presentation was 54.5 years (range: 16 to 81 y). Primary sites were stomach (25 tumors) and distal esophagus (1). The median tumor size was 4.05 cm (range: 0.8 to 19.5 cm). Tumors were composed of lobules of rounded cells with sharp borders, palely eosinophilic to clear cytoplasm, and round nuclei. All tumors involved the muscularis propria, and 12 also involved the serosal surface. Mitoses ranged from <1 to 53/10 HPF (median: 5/10 HPF). Sixteen tumors, including all 15 with mitoses ≥2/10 HPF, showed atypia (3 mild, 10 moderate, 3 severe), defined as spindle cell morphology, nuclear irregularity, nuclear size variability, enlarged nuclei, or coarse chromatin. Considering these histologic features and clinical behavior, tumors were classified as malignant (15 tumors) if they measured ≥5 cm or showed both atypia and mitoses ≥2/10 HPF, or benign (11 tumors) if these criteria were not met. Follow-up was available for 19 patients (73%; range: 1 to 15 y; median: 5.8 y), including 7 with benign tumors and 12 with malignant tumors. Two patients with malignant tumors had metastases at presentation, and 7 developed metastases subsequently. Follow-up was available for 8 of 9 patients with metastatic disease. Two were alive with disease at most recent follow-up. One underwent resection of a liver metastasis, with no subsequent metastases in 3 years of follow-up. Five patients died of metastatic disease. By immunohistochemistry, smooth muscle actin was diffusely positive in all evaluated tumors, and caldesmon and synaptophysin were positive in 94% and 73%, respectively. Sequencing identified NOTCH2 alterations in 4 benign tumors (80%) and 8 malignant tumors (80%), including CARMN :: NOTCH2 fusions in 2 benign and 5 malignant tumors. All 5 sequenced benign tumors lacked complex copy number alterations (CNAs), whereas all 10 sequenced malignant tumors showed complex CNAs, including recurrent loss of 9p21.3 (4/10, variably including CDKN2A / B and MTAP ) and ATRX inactivation (4/10). Complex CNAs were identified in all sequenced tumors that were ≥5 cm, exhibited both cytologic atypia and ≥2 mitoses/10 HPF, involved the serosa or metastasized. We propose that gastroesophageal glomus tumors ≥5 cm or with both atypia and mitoses ≥2/10 HPF should be considered malignant. Copy number analysis might be helpful in borderline cases.

Pathological Significance and Prognostic Role of WWC1 in Upper Urinary Tract Urothelial Cancer.

WW and C2 domain-containing 1 (WWC1) protein is a suppressor of malignancies. However, there is no information on the pathological significance of WWC1 in upper urinary tract cancer (UTUC). In this study, WWC1 immunoreactivity was investigated in 152 non-metastatic UTUC samples. The relationships between WWC1 expression and grade, pT stage, proliferative index (using an antibody to Ki-67), and the immunohistochemical expression of matrix metalloproteinase (MMP)-2 and -9 were evaluated. WWC1 expression was negatively associated with tumor grade and pT stage (p<0.001). Positive expression of WWC1 was a better predictor of the UTUC recurrence and subsequent metastasis, and the multivariate analysis showed that WWC1 expression was a significant predictor of subsequent metastasis (hazard ratio=0.29, p=0.020). WWC1 expression inversely correlated with the proliferative index (odds ratio=2.59, p=0.023) and expression of MMP9 (odds ratio=2.19, p=0.040) but not with MMP2 expression, by multivariate analyses. WWC1 expression was negatively associated with malignant aggressiveness via the suppression of cancer cell proliferation and MMP9 expression in patients with UTUC. This suggests WWC1 to be a useful predictor and novel therapeutic target in patients with UTUC.

A CT-based radiomics model to predict subsequent brain metastasis in patients with ALK-rearranged non-small cell lung cancer undergoing crizotinib treatment.

BackgroundBrain metastasis (BM) comprises the most common reason for crizotinib failure in patients with anaplastic lymphoma kinase (ALK)‐rearranged non–small cell lung cancer (NSCLC). We hypothesize that its occurrence could be predicted by a computed tomography (CT)‐based radiomics model, therefore, allowing for selection of enriched patient populations for prevention therapies.MethodsA total of 75 eligible patients were enrolled from Sun Yat‐sen University Cancer Center between June 2014 and September 2019. The primary endpoint was brain metastasis‐free survival (BMFS), estimated from the initiation of crizotinib to the date of the occurrence of BM. Patients were randomly divided into two cohorts for model training (n = 51) and validation (n = 24), respectively. A radiomics signature was constructed based on features extracted from chest CT before crizotinib treatment. Clinical model was developed using the Cox proportional hazards model. Log‐rank test was performed to describe the difference of BMFS risk.ResultsPatients with low radiomics score had significantly longer BMFS than those with higher, both in the training cohort (p = 0.019) and validation cohort (p = 0.048). The nomogram combining smoking history and the radiomics signature showed good performance for the estimation of BMFS, both in the training (concordance index [C‐index], 0.762; 95% confidence interval [CI], 0.663–0.861) and validation cohort (C‐index, 0.724; 95% CI, 0.601–0.847).ConclusionWe have developed a CT‐based radiomics model to predict subsequent BM in patients with non‐brain metastatic NSCLC undergoing crizotinib treatment. Selection of an enriched patient population at high BM risk will facilitate the design of clinical trials or strategies to prevent BM.

Abstract P1-21-04: The real word study on clinical features and prognostic factors of Chinese breast cancer patients with brain metastasis

Abstract Purpose: we used the real-world data of Chinese patients to describe clinicopathological characteristics of patients with breast cancer brain metastases (BCBM) and to investigate survival after diagnosis of brain metastases (BM). Methods: The clinicopathological characteristics of 700 patients with BCBM at the fifth Medical Center of Chinese PLA General Hospital between 2003 and 2021 were retrospectively reviewed. Information was collected from the electronic medical records, including patient demographics, tumor characteristics, and dates of diagnosis of original breast carcinoma and subsequent metastases. Sites and number of metastatic lesions were also recorded, along with data on treatments and outcomes. The prognostic and predictive effects of these clinicopathological variables in BCBM were analyzed. Results: The median age at diagnosis of primary breast cancer was 44 years (range, 22-80 years) and all patients were female. Among the 700 patients with BCBM, 30.0%, 49.7%, 18.9%, 1.4% had Luminal, HER2 positive, triple-negative and unknown subtypes, respectively. Based on available clinical information, the proportions of extracranial metastasis at diagnosis included bone (63.7%), lymph nodes (61.6%), lung (55.1%), liver (50.1%), the soft tissues of the thoracic wall (26.1%) and bone marrow (4.9%).The median time from the diagnosis of breast cancer to the development of BM was 52.0 months [95% confidence interval (CI), 44.3-59.7], 36.0 months (95%CI, 31.9-40.1), and 29.0 months (95%CI, 22.4-35.6) for patients with Luminal, HER2 positive and triple-negative, respectively (p&amp;lt;0.0001) (Figure 1). The median time from the first recurrence to the diagnosis of BM was 18 months for Luminal subtype (95% CI, 15.3-20.7), 14 months for HER2 positive subtype (95% CI, 12.0-16.0), and 12 months for triple-negative subtype (95% CI, 9.0-15.0), respectively (p&amp;lt;0.0001) (Fig 2). The median survival after the diagnosis of BCBM in Luminal, HER2 positive and triple-negative patients was 11 months (95% CI, 8.7-13.2), 13 months (95% CI, 11.4-14.6) and 7 months (95% CI, 5.7-8.3), respectively(p&amp;lt;0.05) (Fig 3). Patients presenting with a solitary brain metastasis had a longer median survival after the diagnosis of BM than patients who presented with multiple brain metastases (14.0 months versus 9 months, p&amp;lt;0.0001). The median survival time of patients with and without anti-HER2 treatment was 14 months (95% CI, 12.2-15.8) and 9 months (95% CI, 6.1-11.9), respectively (p=0.01) (Fig 4). Patients presenting with leptomeningeal metastasis had shorter time after the diagnosis of BM than patients without leptomeningeal metastasis, which were 5 months (95% CI, 1.8-8.2) and 11 months (95% CI, 9.8-12.2), respectively (p=0.002). Conclusion: Despite the improvement noted with more recent year of diagnosis and treatment, survival following a diagnosis of BCBM remains poor and still needs attention. It is necessary to further explore the comprehensive treatment mode of patients with different types and degrees of brain metastasis in order to provide reference for clinical treatment. Table 1.patient characteristics (n=700)Parametern (%)Mean age, y, at diagnosis (range)44(22-80)Stage at initial diagnosis of cancerI89(12.7)II342(48.9)III167(23.9)IV69(9.9)unknown33(4.7)Molecular subtypesLuminal A/B211(30.0)HER2-positive347(49.7)TNBC132(18.9)Unknown10(1.4)Site of first metastasisBrain128(18.3)Others572(81.7)Number of BM at time of BM diagnosis1189(27.0)248(6.9)≥3454(64.9)Unknown9(1.3)Visceral metastases at diagnosis of BMliver351(50.1)lung386(55.1)bone446(63.7)lymph nodes431(61.6)the soft tissues of the thoracic wall183(26.1)bone marrow34(4.9) Citation Format: Tao Wang, Huiqiang Zhang, Feng Li, Xia Wu, Jinmei Zhou, Shao hua Zhang, Li Bian, Ze fei Jiang. The real word study on clinical features and prognostic factors of Chinese breast cancer patients with brain metastasis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-04.

Abstract P2-08-06: Defining transcriptomic profiles of breast cancer with early lymph node metastases: A FLEX database sub-study

Abstract Introduction: Early lymph node (LN) metastasis often precedes systemic metastasis and corresponds with a 35% decrease in 10-year survival compared to patients without LN metastasis. Understanding biologic pathways involved in early LN metastasis could identify promising drug targets for early-stage breast cancer (EBC) treatment. While tumor size modestly correlates with the probability of clinical or occult axillary metastases, small T1 tumors are often found to have LN metastases, while many large T3 tumors are often LN negative. We compared large tumors without evidence of LN metastasis (pT2-3N0) and small tumors with LN metastasis (pT1N1-3) by whole transcriptome analysis to elucidate molecular biological differences associated with the presence or absence of early LN metastasis at diagnosis. Methods: The FLEX study enrolls patients with EBC who undergo standard of care MammaPrint (MP) and BluePrint (BP) testing, and consent to clinically annotated full transcriptome data collection. MP classifies tumors as having High Risk (HR) or Low Risk (LR) of distant recurrence. MP combined with BP subtype tumors as either Luminal A-type (MP LR; 56.8%), Luminal B-type (MP HR; 36.4%), HER2-type (1.5%), or Basal-type (5.3%). In our primary comparison, 355 patients had small, LN-positive tumors (pT1N1-3), and 235 had large, LN-negative tumors (pT2-3N0). Control groups consisted of small, LN-negative (pT1N0; n=1384) and large, LN-positive tumors (pT2-3N1-3; n=375). R package ‘limma’ was used for quantile normalization and differential gene expression (DGE) analyses. Differentially expressed genes (DEGs) with a false discovery rate &amp;lt; 0.05 and fold change &amp;gt; 1.4 were considered significant for this exploratory analysis. Gene set enrichment analysis (GSEA) was performed using the Hallmark gene sets (MSigDB). Results: Principal component analysis of each sample’s transcriptional profile revealed more gene profile differences between MP risk and BP subtype than by pathological stage. Overall, DGE analysis comparing pT2-3N0 to pT1N1-3 identified 30 DEGs; of which MUCL1 had a &amp;gt; 2-fold decrease. Within MP LR and BP Luminal A-type tumors, no DEGs were identified comparing pT2-3N0 to pT1N1-3. HR tumors had 73 DEGs (33 upregulated and 40 downregulated); two of 40 downregulated genes, including MUCL1, had &amp;gt; 2-fold change. Within Luminal B tumors, 34 DEGs were identified when comparing pT2-3N0 with pT1N1-3, although none had &amp;gt; 2-fold change. Basal and HER2 tumors were not analyzed due to small numbers. GSEA showed upregulated proliferation and oxidative phosphorylation pathways, and downregulated epithelial to mesenchymal transition (EMT) and immune signatures in pT2-3N0 relative to pT1N1-3 tumors overall, within HR, and Luminal B tumors. Conclusion: This study provides a foundation for understanding the mechanisms that promote LN metastasis. Studies have previously correlated LN metastasis with EMT, immune function, and gene overexpression (BCL2L1, AURKA, CDKN2A, MCL1, MYC). While we did not find significant differences in these genes, our results indicated similar differentially regulated pathways. Overall, we found most biological differences within MP HR and Luminal B tumors. Proliferation-related pathways were upregulated and EMT and immune-related pathways were downregulated in pT2-3N0 tumors compared with pT1N1-3 tumors, suggesting these pathways distinguish small, node-positive tumors from large, node-negative tumors and are involved in early LN metastasis. Interestingly, MUCL1 which has been reported to promote migration and invasion in breast cancer, was consistently downregulated in pT2-3N0 relative to pT1N1-3 tumors. Future studies will investigate antineoplastic therapies for EBC that modulate these dysregulated pathways to reduce early LN metastasis and subsequent systemic metastasis. Citation Format: Nibash Budhathoki, Faisal Fa'ak, Nina D'Abreo, Shubhada Dhage, Phyu Phyu Soe, Dennis Holmes, Josien Haan, Shiyu Wang, Patricia Dauer, Andrea Menicucci, William Audeh, Douglas K Marks. Defining transcriptomic profiles of breast cancer with early lymph node metastases: A FLEX database sub-study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-06.

An Immunohistochemical Study on Expression of Laminin5 Gamma2 Chain and Alpha Smooth Muscle actin in Oral Squamous Cell Carcinoma

Background and objectives: Head and neck carcinomas are the biological heterogeneous group of cancers, of which oral cancer is the most common. Ninety percent of oral cancers are squamous cell carcinomas originating from the mucosal epithelium carcinogenesis. Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide. The transformation of the normal epithelial cell into a tumor cell depends upon certain changes that happen at the cellular and molecular level which will help in its survival and proliferation. The basement membrane will show invasion by these altered tumor cells into the connective tissue stroma and then their subsequent spread and metastasis, which is an important prognostic indicator. Laminin-5 is a protein which is found to be associated with a migratory phenotype in epithelial neoplastic cells and also the stromal myofibroblasts play a key role in tumor invasion, due to its ability to modify the extracellular matrix. Aim: Laminin-5 (Ln-5) is the major component of the basement membrane and is involved for tumour progression. Alpha-smooth muscle actin (α-SMA) is an isoform of actin, positive in myofibroblasts and is an epithelial to mesenchymal transition (EMT) marker. EMT is a process by which tumor cells develop and are able to metastasize. Tumor cells progression is always followed by alteration in the cell composition and extracellular matrix .Therefore the aim of this study is to detect and evaluate the expression of laminin5 gamma2 and α-SMA in OSCC and to evaluate the association of density of stromal myofibroblasts with tumour budding intensity. Materials and methods: Thirty paraffin embedded tissue blocks of clinically diagnosed and histopathologically confirmed cases of OSCC were evaluated .In this we have divided them into10 well differentiated OSCC,10 moderately differentiated OSCC and 10 poorly differentiated OSCC for laminin-5 and α- smooth muscle actin (SMA) using standard immunohistochemistry technique. ....

Metastatic Breast Cancer Recurrence after Bone Fractures.

Simple SummaryBone fractures bear potential risk to promote metastatic relapse in breast cancer. We conducted a population-based cohort study of 84,300 breast cancer patients diagnosed between January 2015 and November 2019. Bone fracture after breast cancer diagnosis was associated with an increased metastasis risk. Fractures may pose an increased risk to developing metastasis. Potential clinical implications for cancer patients are in support of fall prevention programs.Experimental studies suggest that bone fractures result in the release of cytokines and cells that might promote metastasis. Obtaining observational data on bone fractures after breast cancer diagnoses related to distant breast cancer recurrence could help to provide first epidemiological evidence for a metastasis-promoting effect of bone fractures. We used data from the largest German statutory health insurance fund (Techniker Krankenkasse, Hamburg, Germany) in a population-based cohort study of breast cancer patients with ICD-10 C50 codes documented between January 2015 and November 2019. The risk of metastasis overall, regional, distant non-bone or bone metastasis related to a fracture was modeled by an adjusted discrete time-to-event analysis with time-dependent exposure. Of 154,000 breast cancer patients, 84,300 fulfilled the inclusion criteria and had a follow-up time of more than half a year. During follow-up, fractures were diagnosed in 13,579 (16.1%) patients. Metastases occurred in 7047 (8.4%) patients; thereof 1544 had affected regional lymph nodes only and 5503 distant metastases. Fractures demonstrated a statistically significant association with subsequent metastasis overall (adjusted HR 1.12, 95% CI 1.04, 1.20). The highest risk for metastasis was observed in patients with subsequent bone metastasis (adjusted HR 1.18, 95% CI 1.05, 1.34), followed by distant non-bone metastasis (adjusted HR 1.16, 95% CI 1.07, 1.26) and lymph node metastasis (adjusted HR 1.08, 95% CI 0.97, 1.21).

IKBKE phosphorylates and stabilizes Snail to promote breast cancer invasion and metastasis.

IKBKE, a non-canonical inflammatory kinase, is frequently amplified or activated, and plays predominantly oncogenic roles in human cancers, especially in breast cancer. However, the potential function and underlying mechanism of IKBKE contributing to breast cancer metastasis remain largely elusive. Here, we report that depletion of Ikbke markedly decreases polyoma virus middle T antigen (PyVMT)-induced mouse mammary tumorigenesis and subsequent lung metastasis. Biologically, ectopic expression of IKBKE accelerates, whereas depletion of IKBKE attenuates breast cancer invasiveness and migration in vitro and tumor metastasis in vivo. Mechanistically, IKBKE tightly controls the stability of transcriptional factor Snail in different layers, in particular by directly phosphorylating Snail, which markedly blocks the E3 ligase β-TRCP1-mediated Snail degradation, resulting in breast cancer epithelial-mesenchymal transition (EMT) and metastasis. These findings together reveal a novel oncogenic function of IKBKE in promoting breast cancer metastasis by governing Snail abundance, and highlight the potential of targeting IKBKE for metastatic breast cancer therapies.

The Interrelation Among Triad of Depth of Invasion, Perineural Invasion and Tumor Size in Squamous Cell Carcinoma of Tongue and Floor of the Mouth: An Analytical Appraisal.

Head and neck cancer represents 5-10% of all malignancies. Squamous cell carcinoma (SCC) of the oral cavity represents about 2% of overall malignant neoplasms and 47% of the head and neck region. Squamous cell carcinoma of tongue has a peculiar behavior of occult and skips metastasis to regional lymph nodes. It occasionally occurs along with floor of the mouth. The purpose of this study is to evaluate the significance of correlation between, depth of invasion of the primary tumor, its proximity with the neurovascular bundle and subsequent perineural invasion and cervical lymph node metastasis in squamous cell carcinoma tongue and floor of the mouth and the sites involving both. A total of 108 patients with carcinoma tongue (59), floor of the mouth (20) and involving both together (29) who underwent treatment during January 2015 to June 2017 that were followed up until December 2019 were assessed. Out of 108 patients that were included in the study, 71 patients underwent primary surgery and 37 patients were inoperable (tongue-17, floor of the mouth-9 and involving both together-11). Perineural invasion was seen in 15 cases of pT1-2 where depth of invasion was less than 1cm and in 28 cases of pT3-4 where depth of invasion was more than 1cm (p-0.075). Skip metastasis was accounted for 61.9% overall. The triad of perineural invasion, depth of invasion and tumor size is interrelated and was responsible for cervical lymph node metastasis and prognosis of the disease. Obtaining clear deep margins of the tumor from the mucosal margin and removal of lympho-fatty tissue at the floor of the mouth is an important aspect which gives the indication about prognostic factors like depth of invasion, tumor size, cervical nodal metastasis and recurrence of the disease. High-grade tumors (T3-4), depth of invasion of tumor at 1cm or > 1cm, increase the propensity of perineural invasion highly.

LncRNA HITT inhibits metastasis by attenuating Rab5-mediated endocytosis in lung adenocarcinoma

Endocytosis of cell surface receptors is essential for cell migration and cancer metastasis. Rab5, a small GTPase of the Rab family, is a key regulator of endosome dynamics and thus cell migration. However, how its activity is regulated still remains to be addressed. Here, we identified a Rab5 inhibitor, a long non-coding RNA, namely HITT (HIF-1α inhibitor at translation level). Our data show that HITT expression is inversely associated with advanced stages and poor prognosis of lung adenocarcinoma patients with area under receiver operating characteristics (ROC) curve (AUC) 0.6473. Further study reveals that both endogenous and exogenous HITT inhibits single-cell migration by repressing β1 integrin endocytosis in lung adenocarcinoma. Mechanistically, HITT is physically associated with Rab5 at switch I via 1248-1347 nt and suppresses β1 integrin endocytosis and subsequent cancer metastasis by interfering with guanine nucleotide exchange factors (GEFs) for Rab5 binding. Collectively, these findings suggest that HITT directly participates in the regulation of Rab5 activity, leading to a decreased integrin internalization and cancer metastasis, which provides important insights into a mechanistic understanding of endocytosis and cancer metastasis.

Epidermal Growth Factor Receptor as Target for Perioperative Elimination of Circulating Colorectal Cancer Cells.

Surgical resection of the tumor is the primary treatment of colorectal cancer patients. However, we previously demonstrated that abdominal surgery promotes the adherence of circulating tumor cells (CTC) in the liver and subsequent liver metastasis development. Importantly, preoperative treatment with specific tumor-targeting monoclonal antibodies (mAb) prevented surgery-induced liver metastasis development in rats. This study investigated whether the epidermal growth factor receptor (EGFR) represents a suitable target for preoperative antibody treatment of colorectal cancer patients undergoing surgery. The majority of patients with resectable colorectal liver metastases were shown to have EGFR + CTCs. Three different anti-EGFR mAbs (cetuximab, zalutumumab, and panitumumab) were equally efficient in the opsonization of tumor cell lines. Additionally, all three mAbs induced antibody-dependent cellular phagocytosis (ADCP) of tumor cells by macrophages at low antibody concentrations in vitro, independent of mutations in EGFR signaling pathways. The plasma of cetuximab-treated patients efficiently opsonized tumor cells ex vivo and induced phagocytosis. Furthermore, neither proliferation nor migration of epithelial cells was affected in vitro, supporting that wound healing will not be hampered by treatment with low anti-EGFR mAb concentrations. These data support the use of a low dose of anti-EGFR mAbs prior to resection of the tumor to eliminate CTCs without interfering with the healing of the anastomosis. Ultimately, this may reduce the risk of metastasis development, consequently improving long-term patient outcome significantly.

Thyroid carcinoma metastases to central nervous system and vertebrae.

Metastatic thyroid carcinoma rarely involves the parenchyma of the central nervous system (CNS) or vertebral bones. While various mutations have been identified in primary thyroid carcinomas and differ based on the histological type, little is known about the molecular features of thyroid carcinoma metastases to brain or spinal column. Based on limited prior literature, we hypothesized that TERT mutations might be enriched in CNS metastatic lesions. CNS/vertebral metastases were identified via database search, 1.01.2006 to 9.08.2021, and mutation/fusion testing performed. 21 surgically resected lesions were identified from 16 patients: 15/21 metastases were to the vertebral bone, requiring neurosurgical intervention for cord compression and 6/21 metastases were intraparenchymal. Male : female ratio was 1 : 1, with median age at the time of CNS metastasis of 62 years. Metastases were of varied histological types, with follicular the most common; the histological subtype often matched in patients with multiple CNS metastases although 2 patients showed dedifferentiation in subsequent metastases. Diagnosis of thyroid carcinoma antedated development of CNS metastases in all but 2 patients in whom a surgically-resected bone metastasis represented their first diagnosis. Intervals for the remaining 14 patients from primary to CNS/vertebral metastasis ranged from 6 months to 41 years. Mutations were multiple in 14/15 cases, including TERT (n = 12) and NRAS (n = 9), with fewer TP53, ATM, AKT1, PTEN, NOTCH1 mutations. Two specimens had fusions involving RET. TERT mutation occurred in a significantly higher percentage (80%) of mutations than reported for primary tumors, underscoring the need for molecular testing of the metastases, should a targeted therapy become available.

Vasculogenic Mimicry-An Overview.

Vasculogenic mimicry (VM), a tumor microcirculation model found in melanoma in the last 20years, is a vascular channel-like structure composed of tumor cells, but without endothelial cells, that stains positive for periodic acid-Schiff (PAS) and negative staining for CD31. VM provides, to the highly aggressive malignant tumor cells, adequate oxygen and nutrient supply for tumor growth and subsequent metastasis process and its presence are related to poor prognosis in patients. VM is independent of endothelial cells, which may partly explain why angiogenesis drug inhibitors have not achieved the expected success for cancer treatment.

Can Acute Postoperative Pain Management After Tumour Resection Surgery Modulate Risk of Later Recurrence or Metastasis?

BackgroundCancer is a leading cause of mortality worldwide, but death is rarely from the primary tumour: Rather it is multi-organ dysfunction from metastatic disease that is responsible for up to 90% of cancer-related deaths. Surgical resection of the primary tumour is indicated in 70% of cases. The perioperative stress response, tissue hypoxia at the site of surgery, and acute pain contribute to immunosuppression and neo-angiogenesis, potentially promoting tumour survival, proliferation, and metastasis. Poorly controlled acute postoperative pain decreases Natural Killer (NK) immune cell activity, which could potentially facilitate circulating tumour cells from evading immune detection. This consequently promotes tumour growth and distal metastasis.MethodsWe conducted a comprehensive literature search for links between acute pain and cancer outcomes using multiple online databases. Relevant articles from January 1st, 2010 to September 1st, 2021 were analysed and appraised on whether postoperative pain control can modulate the risk of recurrence, metastasis, and overall cancer survival.ResultsAlthough experimental and retrospective clinical data suggest a plausible role for regional anaesthesia in cancer outcome modulation, this has not been supported by the single, largest prospective trial to date concerning breast cancer. While there are mixed results on anaesthesiology drug-related interventions, the most plausible data relates to total intravenous anaesthesia with propofol, and to systemic administration of lidocaine.ConclusionThe hypothesis that anaesthetic and analgesic technique during cancer surgery could influence risk of subsequent recurrence or metastasis has been prevalent for >15 years. The first, large-scale definitive trial among women with breast cancer found robust equivalent findings between volatile anaesthesia with opioid analgesia and regional anaesthesia. Therefore, while regional anaesthesia during tumour resection does not seem to have any effect on cancer outcomes, it remains plausible that other anaesthetic techniques (e.g. total intravenous anaesthesia and systemic lidocaine infusion) might influence oncologic outcome in other major tumour resection surgery (e.g. colorectal and lung). Therefore, another large trial is needed to definitively answer these specific research questions. Until such evidence is available, perioperative analgesia for cancer surgery of curative intent should be based on patient co-morbidity and non-cancer endpoints, such as optimising analgesia and minimising postoperative complications.

Incorporating artificial intelligence in urology: Supervised machine learning algorithms demonstrate comparative advantage over nomograms in predicting biochemical recurrence after prostatectomy

After radical prostatectomy (RP), one-third of patients will experience biochemical recurrence (BCR), which is associated with subsequent metastasis and cancer-specific mortality. We employed machine learning (ML) algorithms to predict BCR after RP, and compare them with traditional regression models and nomograms. Utilizing a prospective Uro-oncology registry, 18 clinicopathological parameters of 1130 consecutive patients who underwent RP (2009-2018) were recorded, yielding over 20,000 data points for analysis. The data set was split into a 70:30 ratio for training and validation. Three ML models: Naïve Bayes (NB), random forest (RF), and support vector machine (SVM) were studied, and compared with traditional regression models and nomograms (Kattan, CAPSURE, John Hopkins [JHH]) to predict BCR at 1, 3, and 5 years. Over a median follow-up of 70.0 months, 176 (15.6%) developed BCR, at a median time of 16.0 months (interquartile range [IQR]: 11.0-26.0). Multivariate analyses demonstrated strongest association of BCR with prostate-specific antigen (PSA) (p: 0.015), positive surgical margins (p < 0.001), extraprostatic extension (p: 0.002), seminal vesicle invasion (p: 0.004), and grade group (p < 0.001). The 3 ML models demonstrated good prediction of BCR at 1, 3, and 5 years, with the area under curves (AUC) of NB at 0.894, 0.876, and 0.894, RF at 0.846, 0.875, and 0.888, and SVM at 0.835, 0.850, and 0.855, respectively. All models demonstrated (1) robust accuracy (>0.82), (2) good calibration with minimal overfitting, (3) longitudinal consistency across the three time points, and (4) inter-model validity. The ML models were comparable to traditional regression analyses (AUC: 0.797, 0.848, and 0.862) and outperformed the three nomograms: Kattan (AUC: 0.815, 0.798, and 0.799), JHH (AUC: 0.820, 0.757, and 0.750) and CAPSURE nomograms (AUC: 0.706, 0.720, and 0.749) (p < 0.001). Supervised ML algorithms can deliver accurate performances and outperform nomograms in predicting BCR after RP. This may facilitate tailored care provisions by identifying high-risk patients who will benefit from multimodal therapy.

Clinical effects of cervical conization with positive margins in cervical cancer

Radical surgery after cervical conization is a common approach for the treatment of cervical cancer. In some cases, disease progression is observed after positive margins at conization, but the effect of conization on disease progression remains unclear. Thus, the aim of this study was to investigate the clinical outcomes of positive margins at conization in cervical cancer. A total of 101 patients who underwent cervical conization before radical hysterectomy and pelvic lymph node dissection were considered eligible by reviewing medical records. The association between the positive margins and patient outcomes, including subsequent lymph node metastasis, was evaluated. The rate of lymphovascular space invasion (LVSI) positivity at radical surgery was significantly higher in patients with positive margins (p = 0.017) than in those with negative margins, although there was no significant difference in the rate of pelvic lymph node metastasis (p = 0.155). Moreover, there was no significant difference in the overall survival or progression-free survival between the two groups (p = 0.332 and 0.200, respectively). A positive margin at conization presented no significant prognostic disadvantage; thus, diagnostic conization is one of the most suitable treatment options for early-stage cervical cancer that is difficult to accurately assess.

Molecular Profile Study of Extracellular Vesicles for the Identification of Useful Small “Hit” in Cancer Diagnosis

Tumor-secreted extracellular vesicles (EVs) are the main mediators of cell-cell communication, permitting cells to exchange proteins, lipids, and metabolites in varying physiological and pathological conditions. They contain signature tumor-derived molecules that reflect the intracellular status of their cell of origin. Recent studies have shown that tumor cell-derived EVs can aid in cancer metastasis through the modulation of the tumor microenvironment, suppression of the immune system, pre-metastatic niche formation, and subsequent metastasis. EVs can easily be isolated from a variety of biological fluids, and their content makes them useful biomarkers for the diagnosis, prognosis, monitorization of cancer progression, and response to treatment. This review aims to explore the biomarkers of cancer cell-derived EVs obtained from liquid biopsies, in order to understand cancer progression and metastatic evolution for early diagnosis and precision therapy.

Stat1 confers sensitivity to radiation in cervical cancer cells by controlling Parp1 levels: a new perspective for Parp1 inhibition

Cervical cancer (CC) is the fourth most common cause of cancer-related death in women. According to international guidelines, a standard treatment for locally advanced cervical cancer (LACC) consists of exclusive concurrent chemoradiation treatment (CRT). However, chemoradioresistance and subsequent relapse and metastasis of cancer occur in many patients, and survival for these women has generally remained poor. Therefore, strategies to overcome resistance are urgently needed. We have recently reported a radiosensitizing effect of the signal transducer and activator of transcription 1 (STAT1) in CC, associated with the control of [Poly(ADP-ribose) polymerase −1] PARP1 levels, a key factor in cell response to DNA damage induced by radiation. Here, we sought to decipher the underlying mechanism of STAT1-mediated control of PARP1, elucidating its role as a radiosensitizer in CC. Functional and molecular biology studies demonstrated that STAT1 may act at both transcriptional and posttranscriptional levels to modulate PARP1 expression in CC cells. In light of these results, we tested the effect of Olaparib in sensitizing CC cells to radiation and investigated signaling pathways involved in the activity observed. Results showed that PARP1 inhibition, at clinically achievable doses, may indeed selectively improve the sensitivity of resistant CC cells to DNA-damaging treatment. The translational relevance of our findings was supported by preliminary results in a limited patient cohort, confirming that higher PARP1 levels are significantly associated with a radioresistant phenotype. Finally, bioinformatics analysis of GEPIA and TCGA databases, demonstrated that PARP1 mRNA is higher in CC than in normal tissues and that increased PARP1 mRNA expression levels are associated with poor prognosis of LACC patients. Overall, our data open new opportunities for the development of personalized treatments in women diagnosed with CC.