Invasive Malignant Cells Research Articles

Initial MRI findings predictive of a pathological complete response to neoadjuvant treatments in HER2-positive breast cancers

PurposeThis study aimed to determine if initial MRI findings could predict a pathological complete response (pCR) following neoadjuvant systemic therapy (NST) in HER2-positive breast cancers. MethodsThe study retrospectively included 111 patients (Center 1, training set) and 71 patients (Center 2, validation set) with HER2-positive cancer who underwent NST. Initial clinicopathological data and MRI findings were recorded. Continuous variables were analyzed using the Mann–Whitney and Student’s t-tests, while categorical variables were analyzed using the χ2 or Fisher’s exact test. Univariate analysis was conducted to determine the associations between these variables and pathological complete response (pCR), defined as the absence of invasive malignant cells in the breast and lymph nodes. Interobserver reproducibility was assessed for associated non-mass enhancement (NME) parameter by analyzing 50 MR studies (intraclass correlation coefficient). ResultspCR was achieved in 67 patients, 51 (46 %) from Center 1 and 16 (23%) from Center 2 (p = 0.003), with significant differences between Centers 1 and 2 in tumor-infiltrating lymphocyte levels and lymphovascular invasion (p < 0.001). The initial presence of suspicious associated NME was the only significant parameter predictive of pCR (p < 0.001 for Center 1 and 0.04 for Center 2). The inter-observer reproducibility for this MRI feature was good, with an intraclass correlation coefficient of 0.872 (95 % CI: 0.73–1.00). ConclusionThe presence of suspicious associated NME in HER2-positive cancers on the initial MRI study was predictive of achieving pCR after NST. This significant preliminary finding warrants confirmation through prospective multicenter studies.

LncRNA Biomarkers of Glioblastoma Multiforme.

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14-16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood.

Liver metastatic colonization by invasive cancer cells: a review of potential biomarkers with mitochondrial involvement

The liver, characterized by a unique metabolic and immunosuppressive environment, is also the organ to which invasive malignant cells of many different cancer types most frequently metastasize. The reasons for this organ-specific metastatic process have been investigated for decades. This review first provides an overview of recent breakthroughs in this field, introducing intercellular communication between circulating tumor cells and the heterogeneous cell populations of the liver, and modifications to the extracellular matrix (ECM). Subsequently, to improve the understanding of the molecular mechanisms involved in the metastasis of colorectal cancer to the liver, the second leading cause of cancer-related mortality, the recent literature on this question was analyzed. Among the various parameters involved, the mechanisms behind the activation of hepatic stellate cells, proteins inducing ECM remodeling, specific genomic features of liver metastases, metabolic rewiring, and characteristics of stromal-enriched microenvironments were discussed. To provide more insights into the molecular determinants of liver metastatic colonization, important findings reported on a set of mitochondrial proteins were addressed, the relative abundance of which changed in the liver during the progression stage of an aggressive experimental model of peritoneal malignant mesothelioma in immunocompetent rats. Based on previous studies cross-comparing the liver proteomes from curcumin-treated tumor-bearing rats/untreated tumor-bearing rats/normal rats, data from the literature were reviewed for 25 mitochondrial proteins of interest. Their role in lipid metabolism, heme biosynthesis, the electron transport chain, small molecule transport, mitochondrial dynamics, the tricarboxylic acid cycle, and protection against oxidative stress were analyzed in the context of both cancer and non-malignant liver diseases.

Abstract B039: Identification of sex-specific molecular features in glioma transcriptome

Abstract Glioma is a lethal disease with limited treatment options available. Sex differences in glioma are well-documented in clinical settings, with males having twice the risk of developing the disease and increased mortality compared to female counterparts. To investigate the molecular basis of sex differences in glioma, we analyzed transcriptomic sex differences in a collection of three independent glioma datasets and validated them in additional independent studies. The impact of differentially expressed genes were assessed through Gene Set Enrichment Analysis (GSEA) on approximately 5000 gene sets to interpret their biological relevance. Given the well-recognized heterogeneity of glioma, we also integrated three single-cell RNA (scRNA) sequencing datasets to decipher the sex differences in cellular composition and cell-type specific differential gene expression between male and female tumors. The effects of sex on gene expression are modest and primarily driven by the X chromosome (14 out of 16 differentially expressed genes were on the X chromosome). These genes are associated with escape from X-chromosome inactivation (e.g., KDM5C, KDM6A) and are also sex-differentially expressed (DE) in the healthy human brain according to Genotype-Tissue Expression (GTEx) data. GSEA results suggest increased activity in cell proliferation and neuronal signaling in male GBM samples, whereas females show enrichment in glycoprotein/lipid metabolism. By deconvoluting the cell-type composition, we identified a higher percentage of pericytes in the male glioma tumor microenvironment compared to those in females, which is consistent with recent spatial-omic discoveries in glioma. By integrating scRNA sequencing data, we found that both differentially expressed genes and pathways show cell-type-specific enrichment. For example, the female-biased gene GBGT1 is exclusively expressed in the myeloid lineage, while male-biased neuronal pathways are enriched in cancer stem cells. Integrating with the inference of cell trajectories, we observed that male tumors harbor more unconnected, invasive malignant cells than females, which might explain the poor prognosis in male glioma patients. In summary, our results provide a comprehensive multi-level characterization of sex differences in glioma tumors, and these findings will provide novel insights into glioma disease progression and development of new therapy. Citation Format: Yingbo Huang, Yuting Shan, Weijie Zhang, Christina Printzis, Lorenzo Pesce, Barbara Elaine Stranger, R. Stephanie Huang. Identification of sex-specific molecular features in glioma transcriptome [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B039.

Lactoferrin is a natural inhibitor of plasminogen activation

The plasminogen system is essential for dissolution of fibrin clots, and in addition, it is involved in a wide variety of other physiological processes, including proteolytic activation of growth factors, cell migration, and removal of protein aggregates. On the other hand, uncontrolled plasminogen activation contributes to many pathological processes (e.g. tumor cells' invasion in cancer progression). Moreover, some virulent bacterial species (e.g. Streptococci or Borrelia) bind human plasminogen and hijack the host's plasminogen system to penetrate tissue barriers. Thus, the conversion of plasminogen to the active serine protease plasmin must be tightly regulated. Here, we show that human lactoferrin, an iron-binding milk glycoprotein, blocks plasminogen activation on the cell surface by direct binding to human plasminogen. We mapped the mutual binding sites to the N-terminal region of lactoferrin, encompassed also in the bioactive peptide lactoferricin, and kringle 5 of plasminogen. Finally, lactoferrin blocked tumor cell invasion in vitro and also plasminogen activation driven by Borrelia Our results explain many diverse biological properties of lactoferrin and also suggest that lactoferrin may be useful as a potential tool for therapeutic interventions to prevent both invasive malignant cells and virulent bacteria from penetrating host tissues.

Gallbladder polyps in familial adenomatous polyposis

Introduction Familiar adenomatous polyposis (FAP) is an inherited autosomal dominant disease characterized by the development of hundreds to thousands of colorectal adenomas in young adults. If left untreated, the patients develop colorectal cancer by age of 40. This disorder is caused by germline mutation of the adenomatous polyposis coli (APC) gene located on the chromosome 5q21. FAP can be associated with occur of various extracolonic malignancies, especially ampullary adenocarcinoma. As well it has been described an association between FAP, thyroid cancer and biliary system neoplasia. We present a rare case of multifocal gallbladder polyps in association with familial adenomatous polyposis. Case report We present the case of a 39-year-old male patient with the FAP-Syndrome. He had undergone a total colectomy with ileoanal pouch reconstruction years ago. In the current history, he reported about chronic abdominal pain in the right upper abdomen with postprandial nausea. The clinical examination at the admission showed no palpable mass or tenderness in the abdomen. The laboratory tests were normal. Abdominal ultrasound showed four concrements and multiple small polyps. He underwent laparoscopic cholecystectomy. The postoperative course was uneventful. Results and conclusions The mucosal inspection at the histopathological examination showed more than 80 green polypoid lesions. Microscopically were classified tubular adenomas with mostly low–grade but focally with high-grade epithelial dysplasia cells. Their epithelium was predominantly of the biliary type. No invasive malignant cells have been described. Immunohistochemical staining with s-catenin showed strong positivity for cytoplasmic and nuclear expression. APC is closely connected to s-catenin and a nuclear expression comes along with s-catenin mutations. Nuclear staining has been described in adenocarcinomas and late adenomas with severe dysplasia. Take-home message FAP is the most common adenomatous polyposis syndrome characterized by the development of numerous colorectal adenomatous polyps. It is associated with greater risk of developing upper gastrointestinal malignancy or extraintestinal cancer. Due to previous reports and our conclusions, a simultaneous prophylactic cholecystectomy should be performed by FAP patients, who undergo colectomy, to eliminate the risk of gallbladder neoplasia.

Epithelial/myoepithelial carcinoma of breast: A report of hitherto unreported case

Herein reported is the first case of epithelial/myoepithelial carcinoma (EMC) of breast. An 83-year-old woman noticed a circa 1.0 cm tumor of left breast. Core needle biopsies were diagnosed as invasive ductal carcinoma. Mastectomy with axillary lymph node dissection was performed, and gross examination revealed a circa 1 cm × 1 cm tumor. Microscopically, the tumor was composed of invasive malignant cells forming tubular or cords structures with a scirrhous collagenous stroma. The malignant cells were composed by the following two elements; one was malignant epithelial cells and the other was malignant myoepithelial cells with clear or vacuolated cytoplasm. Immunohistochemically, the myoepithelial element was positive for p63, CD10, cytokeratin (CK) 34BE12, and CK5/6, S100 protein and alpha-smooth muscle actin. Both elements were positive for CK7, p53, and Ki67 (labeling: 16%), estrogen receptor, progesterone receptor. Both elements were negative for CK20 and HER2/neu. The sentinel and level 1 lymph node were negative for metastasis (0/6). The tumor was pT1pN0cM0 and the stage was stage 1. The patient had booster hormone therapy and is now alive 14 months without recurrence after the operation.

Malignant melanoma in a Dog - A Case report

Introduction Veterinary Surgery and Radiology, College of Veterinary Science, Sri Venkateswara Veterinary The oral cavity is the fourth most common site of University, Tirupati with the history of growth over the neoplasia in dogs and malignant melanoma and rd hard palate in between the 3 premolar since 3 months. squamous cell carcinoma are the most common type of Slowly it had grown in size. The growth dark in color, tumors in this site [1]. In dogs, oral malignant firm and hard to touch (Figure-1). The animal showed melanomas most commonly arise from the gingiva, excessive salivation, difficult in prehension and but also can originate from the palatine, labial or mastication was noticed. buccal mucosa [2]. Malignant melanomas are Fine needle aspiration cytology revealed characteristically rapidly growing, locally invasive malignant cells appear as round or fusiform, with tumors that metastasize early in the course of the eccentric nuclei with dark black or brown color, small disease [3]. These tumors are widely recognized as a pigmented cytoplasm (Figure-2). Haematological, tumor of older dogs and are common in male than in biochemical parameters were within the normal female dogs. Melanomas were overrepresented in physiological limits. It was diagnosed as a tumor and smaller breeds such as cocker spaniels and miniature was decided to perform surgery. poodles [4]. A case of surgical management of Treatment malignant melanoma in the hard palate of a dog was The dog was premedicated with Atropine discussed here. Sulphate @ 0.04 mg/kg body weight subcutaneously Case History and Observations and sedated with Xylazine Hydrochloride 1.0 mg/kg A five years old non descriptive breed dog was body weight intra-muscularly. General anaesthesia brought to the college clinics, Department of was using Ketamine Hydrochloride @ 5.0 mg/kg body Vet. World, 2012, Vol.5(7):431-432 CLINICAL

Nm23-H1 regulates contact inhibition of locomotion which is affected by ephrin-B1

Contact inhibition of locomotion (CIL) is the process by which cells stop the continual migration in the same direction after collision with another cell. Highly invasive malignant cells exhibit diminished CIL when they contact stromal cells, which allows invasion of the tissue by tumors. We show that Nm23-H1 is essential for the suppression of Rac1 through inactivation of Tiam1 at the sites of cell-cell contact, which plays a pivotal role in CIL. U87MG cells show CIL when they contact normal glia. In spheroid confrontation assays U87MG cells showed only limited invasion of the glial population, but reduction of Nm23-H1 expression in U87MG cells abrogated CIL resulting in invasion. In U87MG cells, Nm23-H1 is translocated to the sites of contact with glia through association with α-catenin and N-cadherin. Mutants of Nm23-H1, which lacked the binding ability with Tiam1, or α-catenin did not restore CIL. Moreover, the expression of ephrin-B1 in tumor cells disrupted CIL and promoted invasion. As one mechanism, ephrin-B1 inhibits the association of Nm23-H1 with Tiam1, which contributes for activation of Rac1. These results indicate a novel function of Nm23-H1 to control CIL, and its negative regulation by ephrin-B1.

Collective Migration Behaviors of Human Breast Cancer Cells in 2D

Cancer related deaths are mainly attributed to the spread of cancer cells to distant organs to form secondary tumors by a process called metastasis. Migration is one of the factors among many others that are strongly implicated in this phenomenon. Here we studied the migratory behavior of benign (MCF-10A), non-invasive malignant (MCF-7) and highly-invasive malignant (MDA-MB-231) tumor cell lines which are derivatives of ductal epithelium of the human breast, using a modified ring cell migration assay technique. Time lapse phase contrast video microscopy was used to monitor migration on both culture coated and Collagen-IV coated surfaces. Individual cells were tracked for 24 h and observations were made on the morphological development of the lamellipods. Analyses show that an intact intercellular adhesion coupled with unidirectional lamellipod formation in benign cells help to coordinate migratory behavior when compared against the malignant variants. Among the cancer cell lines, the non-invasive malignant cells had shorter migratory distances and exhibited pseudo-coordinated behavior due to altered or defective lamellipod morphology and intercellular adhesion, while the highly invasive malignant cells displayed individualistic and chaotic movements with little or no intercellular adhesion. Collagen-IV coating increased the migration rates of the highly invasive cell lines, while the effect was less pronounced on the other two cell lines.

Genistein Increases Epidermal Growth Factor Receptor Signaling and Promotes Tumor Progression in Advanced Human Prostate Cancer

Genistein is an isoflavone found in soy, and its chemo-preventive and -therapeutic effects have been well established from in vitro studies. Recently, however, its therapeutic actions in vivo have been questioned due to contradictory reports from animal studies, which rely on rodent models or implantation of cell lines into animals. To clarify in vivo effects of genistein in advanced prostate cancer patients, we developed a patient-derived prostate cancer xenograft model, in which a clinical prostatectomy sample was grafted into immune deficient mice. Our results showed an increased lymph node (LN) and secondary organ metastases in genistein-treated mice compared to untreated controls. Interestingly, invasive malignant cells aggregated to form islands/micrometastasis only in the secondary organs of the genistein-treated groups, not in the untreated control group. To understand the underlying mechanism for metastatic progression, we examined cell proliferation and apoptosis on paraffin-sections. Immunohistological data show that tumors of genistein-treated groups have more proliferating and fewer apoptotic cancer cells than those of the untreated group. Our immunoblotting data suggest that increased proliferation and metastasis are linked to enhanced activities of tyrosine kinases, EGFR and its downstream Src, in genistein-treated groups. Despite the chemopreventive effects proposed by earlier in vitro studies, the cancer promoting effect of genistein observed here suggests the need for careful selection of patients and safer planning of clinical trials.

Elevated levels of ornithine decarboxylase cooperate with Raf/ERK activation to convert normal keratinocytes into invasive malignant cells

Ornithine decarboxylase (ODC) overexpression coupled with activated Ras is fully sufficient to oncogenically transform primary keratinocytes. To determine the Ras effector pathways that represent the minimal essential contribution to full oncogenic transformation in this context, we evaluated the cooperativity of different Ras effector mutants with overexpressed ODC in an in vivo tracheal xenotransplantation assay for epithelial cell invasiveness. Primary keratinocytes, isolated from either K6/ODC transgenic mouse skin (expressing increased ODC) or from normal littermate skin were infected with retrovirus producing an activated RasV12 or partial loss-of-function effector mutants of RasV12 that selectively induce only the Raf/ERK, RalGDS, or the PI3-kinase signaling pathway. Whereas keratinocytes expressing a fully activated RasV12 are not invasive in tracheal xenotransplants, ODC-overexpressing keratinocytes acquire an invasive phenotype with additional expression of either RasV12 or activation of the Raf/ERK pathway. Independent of a mutated ras, elevated levels of ODC activate the Akt/mTOR signaling pathway as well as the Rho/Rac pathway in primary keratinocytes. Thus, Raf/ERK signaling is sufficient to cooperate with increased ODC activity in the conversion of normal keratinocytes to invasive cells. In order to promote invasiveness in keratinocytes, elevated levels of ODC may cooperate with Raf/ERK via activation of the Akt and Rho/Rac signaling pathway.

Identification of spasmolytic polypeptide expressing metaplasia (SPEM) in remnant gastric cancer and surveillance postgastrectomy biopsies.

Following gastrectomy, the remnant oxyntic mucosa is at increased risk of developing adenocarcinoma. Alkaline pancreaticoduodenal reflux, carcinogen production from intragastric bacterial overgrowth, denervation, and devascularization have been implicated in this malignant transformation. Recent reports have described a novel spasmolytic polypeptide (SP) expressing metaplastic lineage designated as SPEM. This lineage has been identified in the mucosa surrounding gastric adenocarcinomas, and SP staining has been observed in the cells of surface dysplasia and invasive malignancy. In this study we describe 19 cases of remnant gastric adenocarcinoma from Japan. In addition, we studied surveillance biopsies in 90 patients who underwent antrectomy for carcinoma. SPEM was identified in the mucosa surrounding 88% of the remnant cancers, as well as in 61% of the surveillance biopsies. In the malignant resections, 67% of the surface dysplasia displayed SP positive cells, and 25% revealed SP immunostaining within invasive malignant cells. These findings implicate SPEM as a potential precursor lesion of gastric adenocarcinoma.

Pregnancy as a model of controlled invasion might be attributed to the ratio of CD3/CD8 to CD56.

Pregnancy can be considered as a model of successfully controlled tissue invasion. Cellular mediated immunity appears to regulate the controlled invasion of fetal trophoblast cells. In endometrium cancer, a dysregulation of invasive malignant cells can be observed. Since immunocompetent cells are known to be involved in recognition and rejection of 'non-self' antigens, we investigated the presence and distribution pattern of CD3, CD8, CD56, and CD68 positive cells in decidua from normal and failing pregnancies, compared with malignant and benign endometrium. Decidual tissue from first trimester normal pregnancies (NP; n = 15) and abortion (AB; n = 12), endometrial samples from premenopausal women (NE; n = 8), and endometrioid adenocarcinoma (EA; n = 8) were examined by immunohistochemistry using monoclonal antibody against large spectrum cytokeratin, and against the receptors CD3, CD8, CD56 and CD68, respectively. In NP, we observed 32.5% CD3, 44.7% CD56, and 22.9% CD68+ cells. In AB, we found 36.9% CD3, 45.3% CD56, and 17.8% CD68+ cells. The differences in ratio between normal pregnancy and abortion were not statistically significant. In NE, we counted 39.5% CD3, 30.2% CD56 and 30.2% CD68 cells. In EA, we observed 47.9% CD3, 12.4% CD56 and 39.7% CD68+ cells. The decrease of CD56 positive cells in endometrioid adenocarcinoma was statistically significant. Interestingly, we found 4.1% of cells positive for CD8 in NP, 4.9% in AB, 22.7% in NE, and 48.2% in EA. The increase of CD8 cells in NE, and particularly in EA, and decrease of CD56 cells, compared with NP or AB, suggests an interaction between CD8 cells and CD56 cells. Studying different pathological situations in the uterus, such as malignancies or ectopic pregnancies, might help us to understand the mechanisms involved in the maintenance of pregnancy.

Phagocytic capacity of invasive malignant cells in three-dimensional culture.

To study the phagocytic capacity of invasive malignant cells, fragments of the hypoblast from chick blastoderms were confronted in three-dimensional culture with spheroidal aggregates of 1) malignant virally transformed C3H mouse cells (MO4), 2) HeLa cells and 3) embryonic chick heart cells. The hypoblast was used because it contains yolk, a marker that is absent in the confronting cells and that can be identified histologically and ultrastructurally. The confronting tissues were incubated on semi-solid agar-agar medium or in fluid medium on a gyrotory shaker. Cultures were followed for 1 to 7 days by stereomicroscopy, cinemicrophotography, light and transmission electron microscopy. Confrontation with MO4 cells of HeLa cells, known to be invasive in vitro, led to complete disappearance of the hypoblast. The fragments of hypoblast were well conserved when cultured alone or confronted with aggregates of chick heart cells. Degeneration of the hypoblast is shown at the area of contact with MO4-cell or HeLa-cell aggregates, in contrast to heart cells. Filopodia-like extensions from the MO4 or HeLa cells penetrate intercellularly, transcellularly and intracellularly into the hypoblast. Phagosomes, containing yolk and unidentified debris are observed in MO4 cells and in HeLa cells, but not in heart cells. These observations demonstrate the phagocytic capacity of invasive malignant cells.