Insight into brain sex differences of typically developed infants and brain pathologies: A systematic review.

The continually advancing landscape of neuroscientific and imaging research has broadened our comprehension of sex differences encoded in the human brain, expanding from the hypothalamus and sexual behaviour to encompass the entire brain, including its diverse lobes, structures, and functions. However, less is known about sex differences in the brains of neonates and infants, despite their relevance to various sex-linked diseases that develop early in life. In this review, we provide a synopsis of the literature evidence on sex differences in the brains of neonates and infants at the morphological, structural and network levels. We also briefly overview the present evidence on the sex bias in some brain disorders affecting infants and neonates.

Association between vitamin D deficiency and multiple sclerosis- MRI significance: A scoping review.

Background/Objective: Multiple Sclerosis is a common demyelinating disease of the central nervous system. Several studies suggested a link between vitamin D deficiency and multiple sclerosis disease activity, which can be evaluated by magnetic resonance imaging. Thereby, the main objective of the following scoping review is to summarize the magnetic resonance imaging findings assessing the probable effects of vitamin D on MS disease activity. Methodology: PRISMA checklist for systematic reviews and meta-analyses was employed to structure this review. Literature was searched for observational and clinical studies tackling the given matter using several search engines including PubMed, CORE, and Embase. Data was extracted in a systematic manner, and the articles meeting the inclusion criteria were quality-assessed by Jadad scale for randomized clinical trials (RCTs) and Newcastle-Ottawa scale for observational studies. Results: A total of 35 articles were included. Twenty-one (60%) studies noted a statistically significant association between vitamin D and Multiple Sclerosis MRI-detected disease activity. MRI-detected features involved lower contrast-enhancing T1 lesions, lower hyperintense T2 lesions, and a decrease in lesions volume. On the other hand, 40% (14 articles) of the articles did not detect any significant effect of vitamin D on Multiple Sclerosis disease activity. Due to the heterogeneity of the studies involved, meta-analysis was not employed in the given review. Discussion/conclusion: There was an abundance in the number of research studies investigating the relationship between vitamin D and Multiple Sclerosis while highlighting the significant role of MRI in assessing the activity of the disease. Numerous studies found that higher serum vitamin D levels are associated with decreased new active cortical and subcortical lesions and lower lesions volume. These findings highlight the importance of imaging modalities in the various aspects of neurological diseases and encourage further research to focus on the preventive effects of vitamin D on MS patients.

High fat diet exacerbates long-term metabolic, neuropathological, and behavioral derangements in an experimental mouse model of traumatic brain injury.

AIMS: Traumatic brain injury (TBI) constitutes a serious public health concern. Although TBI targets the brain, it can exert several systemic effects which can worsen the complications observed in TBI subjects. Currently, there is no FDA-approved therapy available for its treatment. Thus, there has been an increasing need to understand other factors that could modulate TBI outcomes. Among the factors involved are diet and lifestyle. High-fat diets (HFD), rich in saturated fat, have been associated with adverse effects on brain health. MAIN METHODS: To study this phenomenon, an experimental mouse model of open head injury, induced by the controlled cortical impact was used along with high-fat feeding to evaluate the impact of HFD on brain injury outcomes. Mice were fed HFD for a period of two months where several neurological, behavioral, and molecular outcomes were assessed to investigate the impact on chronic consequences of the injury 30 days post-TBI. KEY FINDINGS: Two months of HFD feeding, together with TBI, led to a notable metabolic, neurological, and behavioral impairment. HFD was associated with increased blood glucose and fat-to-lean ratio. Spatial learning and memory, as well as motor coordination, were all significantly impaired. Notably, HFD aggravated neuroinflammation, oxidative stress, and neurodegeneration. Also, cell proliferation post-TBI was repressed by HFD, which was accompanied by an increased lesion volume. SIGNIFICANCE: Our research indicated that chronic HFD feeding can worsen functional outcomes, predispose to neurodegeneration, and decrease brain recovery post-TBI. This sheds light on the clinical impact of HFD on TBI pathophysiology and rehabilitation as well.

STAT3 in medulloblastoma: a key transcriptional regulator and potential therapeutic target.

Medulloblastoma is the most common malignant brain tumor of childhood accounting for about 60% of all pediatric embryonal tumors. Despite improvements in the overall survival rate, this tumor still lacks an efficient, reliable, and less toxic therapeutic approach. Characterization of the molecular mechanisms involved in medulloblastoma initiation and progression is a crucial step for the development of effective therapies. Signal transducer and activator of transcription 3 is a convergence point for several signaling cascades that are implicated in medulloblastoma tumorigenesis. Accumulated evidence has revealed the pivotal role of signal transducer and activator of transcription 3 in medulloblastoma pathogenesis such as proliferation, survival, angiogenesis, and immunosuppression as well as maintenance, drug resistance, and recurrence. In this review, we focus on the role of signal transducer and activator of transcription 3 in medulloblastoma tumorigenesis and discuss the recent advances of signal transducer and activator of transcription 3 inhibition as a promising developed strategy for medulloblastoma therapy.

Immunohistochemical assessment of cannabinoid type-1 receptor (CB1R) and its correlation with clinicopathological parameters in glioma.

Background: Glioma is the most frequent primary brain tumor and one of the most aggressive forms of cancer. Recently, numerous studies have focused on cannabinoids as a new therapeutic approach due to their antineoplastic effects through activation of the cannabinoid receptors. This study aimed to investigate the immunohistochemical expression level of cannabinoid type-1 receptors (CB1R) in human glioma samples and evaluate its clinicopathologic significance. Materials and methods: We analyzed the expression of CB1R in 61 paraffin-embedded glioma and 4 normal brain tissues using automated immunohistochemical assay. CB1R expression was categorized into high versus low expression levels. Statistical analyses were performed to evaluate the association between CB1R and phosphorylated extracellular signal-related kinase (p-ERK) expression levels and the clinicopathologic features of glioma. Results: Our results showed that CB1R immunopositivity was seen in 59 of 61 cases (96.7%). CB1R was down-expressed in glioma compared to normal brain tissues. However, CB1R expression was not correlated with clinicopathological parameters except for p-ERK. Conclusion: Our findings indicate the down-expression of CB1R in glioma tissues when compared to non-cancerous brain tissues. This change in CB1R expression in gliomas should be further tested regardless of the clinicopathological findings to provide a therapeutic advantage in glioma patients.

Targeting Angiogenic Factors for the Treatment of Medulloblastoma.

OPINION STATEMENT: Medulloblastoma (MB) is the most frequent pediatric brain tumor. Despite conventional therapy, MB patients have high mortality and morbidity rates mainly due to the incomplete understanding of the molecular and cellular processes involved in development of this cancer. Similar to other solid tumors, MB demonstrated high endothelial cell proliferation and angiogenic activity, wherein new blood vessels arise from the pre-existing vasculature, a process named angiogenesis. MB angiogenesis is considered a hallmark for MB development, progression, and metastasis emphasizing its potential target for antitumor therapy. However, angiogenesis is tightly regulated by a set of angiogenic factors making it a complex process to be targeted. Although agents targeting these factors and their receptors are early in development, the potential for their targeting may translate into improvement in the clinical care for MB patients. In this review, we focus on the most potent angiogenic factors and their corresponding receptors, highlighting their basic properties and expression in MB. We describe their contribution to MB tumorigenesis and angiogenesis and the potential therapeutic targeting of these factors.

Western and ketogenic diets in neurological disorders: can you tell the difference?

The prevalence of obesity tripled worldwide between 1975 and 2016, and it is projected that half of the US population will be overweight by 2030. The obesity pandemic is attributed, in part, to the increasing consumption of the high-fat, high-carbohydrate Western diet, which predisposes to the development of the metabolic syndrome and correlates with decreased cognitive performance. In contrast, the high-fat, low-carbohydrate ketogenic diet has potential therapeutic roles and has been used to manage intractable seizures since the early 1920s. The brain accounts for 25% of total body glucose metabolism and, as a result, is especially susceptible to changes in the types of nutrients consumed. Here, we discuss the principles of brain metabolism with a focus on the distinct effects of the Western and ketogenic diets on the progression of neurological diseases such as epilepsy, Parkinson's disease, Alzheimer's disease, and traumatic brain injury, highlighting the need to further explore the potential therapeutic effects of the ketogenic diet and the importance of standardizing dietary formulations to assure the reproducibility of clinical trials.

New insights into the role of fibroblast growth factors in Alzheimer's disease.

Alzheimer's disease (AD), acknowledged as the most common progressive neurodegenerative disorder, is the leading cause of dementia in the elderly. The characteristic pathologic hallmarks of AD-including the deposition of extracellular senile plaques (SP) formation, intracellular neurofibrillary tangles, and synaptic loss, along with prominent vascular dysfunction and cognitive impairment-have been observed in patients. Fibroblast growth factors (FGFs), originally characterized as angiogenic factors, are a large family of signaling molecules that are implicated in a wide range of biological functions in brain development, maintenance and repair, as well as in the pathogenesis of brain-related disorders including AD. Many studies have focused on the implication of FGFs in AD pathophysiology. In this review, we will provide a summary of recent findings regarding the role of FGFs and their receptors in the pathogenesis of AD, and discuss the possible opportunities for targeting these molecules as novel treatment strategies in AD.

Distribution of Primary Brain Tumor Subtypes in Lebanon: A Multicenter Eleven-Year Study of 695 Patients.

Background Brain tumors are associated with relatively high mortality and morbidity in comparison with their low incidence. Little is known about primary brain tumors in Lebanon, as well as in the Arab world. This study aims to analyze the epidemiology of brain tumors across the Lebanese population. Methods Data from pathology reports of patients diagnosed with malignant and non-malignant primary brain tumors were collected retrospectively in an eleven-year period (2007-2017) from four medical centers in Lebanon. A total of 695 primary brain tumor cases (61% malignant and 39% non-malignant) were retrieved from different regions across the country. Results Meningiomas were the most common histology in this sample (29.6%), followed by glioblastomas (25.5%) and oligodendrogliomas (5.9%). Pituitary tumors were only 3.5% of brain tumors. Besides, the most common anatomical locations in malignant and non-malignant tumors were cerebral meninges (29.6%), the "other brain" category (21.3%), and the frontal lobe (11.2%). In children and adolescents, embryonal tumors (21%) were the most common histologies, while glioblastomas and meningiomas accounted for 14.8% and 13.6%, respectively. Conclusion Lebanon presented a low rate of pituitary tumors and an unusually high percentage of malignant tumors, as well as pediatric glioblastomas and meningiomas. This should raise major concerns for policymakers to detect the possible underlying causes.

Biomarkers in Neuroblastoma: An Insight into Their Potential Diagnostic and Prognostic Utilities.

OPINION STATEMENT: Neuroblastoma (NB) is a heterogeneous solid tumor of the pediatric population that originates from neural crest cells and affects the developing sympathetic nervous system. It is the most common neuroblastic tumor accounting for approximately 10% of all childhood cancers and 10-15% of pediatric tumor mortalities. The outcomes range from spontaneous tumor regression in low-risk groups to metastasis and death even after multimodal therapy in high-risk groups. Hence, the detection of NB at an early stage improves outcomes and provides a better prognosis for patients. Early detection and prognosis of NB depend on specific molecules termed biomarkers which can be tissue-specific or circulating. Certain biomarkers are employed in the classification of NB into different groups to improve the treatment and prognosis, and others can be used as therapeutic targets. Therefore, novel biomarker discovery is essential for the early detection of NB, predicting the course of the disease, and developing new targeted treatment strategies. In this review, we aim to summarize the literature pertinent to some important biomarkers of NB and discuss the prognostic role of these biomarkers as well as their potential role in targeted therapy.

Immunosuppression in Medulloblastoma: Insights into Cancer Immunity and Immunotherapy.

OPINION STATEMENT: Medulloblastoma (MB) is the most common pediatric brain malignancy, with a 5-year overall survival (OS) rate of around 65%. The conventional MB treatment, comprising surgical resection followed by irradiation and adjuvant chemotherapy, often leads to impairment in normal body functions and poor quality of life, especially with the increased risk of recurrence and subsequent development of secondary malignancies. The development and progression of MB are facilitated by a variety of immune-evading mechanisms such as the secretion of immunosuppressive molecules, activation of immunosuppressive cells, inhibition of immune checkpoint molecules, impairment of adhesive molecules, downregulation of the major histocompatibility complex (MHC) molecules, protection against apoptosis, and activation of immunosuppressive pathways. Understanding the tumor-immune relationship in MB is crucial for effective development of immune-based therapeutic strategies. In this comprehensive review, we discuss the immunological aspect of the brain, focusing on the current knowledge tackling the mechanisms of MB immune suppression and evasion. We also highlight several key immunotherapeutic approaches developed to date for the treatment of MB.

Immunotherapies for Neurodegenerative Diseases.

The current treatments for neurodegenerative diseases are mostly symptomatic without affecting the underlying cause of disease. Emerging evidence supports a potential role for immunotherapy in the management of disease progression. Numerous reports raise the exciting prospect that either the immune system or its derivative components could be harnessed to fight the misfolded and aggregated proteins that accumulate in several neurodegenerative diseases. Passive and active vaccinations using monoclonal antibodies and specific antigens that induce adaptive immune responses are currently under evaluation for their potential use in the development of immunotherapies. In this review, we aim to shed light on prominent immunotherapeutic strategies being developed to fight neuroinflammation-induced neurodegeneration, with a focus on innovative immunotherapies such as vaccination therapy.

Deciphering the roles of glycogen synthase kinase 3 (GSK3) in the treatment of autism spectrum disorder and related syndromes.

Autism spectrum disorder (ASD) is a complex and multifactorial neurodevelopmental disorder characterized by the presence of restricted interests and repetitive behaviors besides deficits in social communication. Syndromic ASD is a subset of ASD caused by underlying genetic disorders, most commonly Fragile X Syndrome (FXS) and Rett Syndrome (RTT). Various mutations and consequent malfunctions in core signaling pathways have been identified in ASD, including glycogen synthase kinase 3 (GSK3). A growing body of evidence suggests a key role of GSK3 dysregulation in the pathogenesis of ASD and its related disorders. Here, we provide a synopsis of the implication of GSK3 in ASD, FXS, and RTT as a promising therapeutic target for the treatment of ASD.

Drug Repurposing in Medulloblastoma: Challenges and Recommendations.

OPINION STATEMENT: Medulloblastoma is the most frequently diagnosed primary malignant brain tumor among children. Currently available therapeutic strategies are based on surgical resection, chemotherapy, and/or radiotherapy. However, majority of patients quickly develop therapeutic resistance and are often left with long-term therapy-related side effects and sequelae. Therefore, there remains a dire need to develop more effective therapeutics to overcome the acquired resistance to currently available therapies. Unfortunately, the process of developing novel anti-neoplastic drugs from bench to bedside is highly time-consuming and very expensive. A wide range of drugs that are already in clinical use for treating non-cancerous diseases might commonly target tumor-associated signaling pathways as well and hence be of interest in treating different cancers. This is referred to as drug repurposing or repositioning. In medulloblastoma, drug repurposing has recently gained a remarkable interest as an alternative therapy to overcome therapy resistance, wherein existing non-tumor drugs are being tested for their potential anti-neoplastic effects outside the scope of their original use.

Prognostic impact of adenylyl cyclase-associated protein 2 (CAP2) in glioma: A clinicopathological study.

BACKGROUND: Gliomas are a group of diseases arising from intracranial neoplastic tissues that produce a wide spectrum of clinicopathological features and morphological changes. Key questions that intrigue neuro-oncology researchers include defining novel oncophenotypic signatures relevant to diagnosing such tumors and predicting prognoses among patients. One of the key regulators of the cellular actin dynamics is adenylyl cyclase-associated protein 2 (CAP2), a protein that has been studied before in the milieu of cancer and shown to be associated with tumor progression; yet, its expression levels in the context of gliomas have not been assessed. Hence, we were interested in investigating CAP2 expression in gliomas and evaluating its clinicopathological and prognostic significance. MATERIALS AND METHODS: CAP2 expression at the protein level was analyzed in 47 human paraffin-embedded gliomas and normal brain tissues by automated immunohistochemical analysis. Statistical analysis was also performed to assess CAP2 expression level in normal and tumor tissues, and to evaluate its clinicopathological and prognostic significance. RESULTS: Our results revealed high expression of CAP2 protein in tumors of gliomas compared to normal tissues and normal areas adjacent to tumors. High expression of CAP2 was also associated with advanced tumor grades among gliomas. Kaplan-Meier analysis revealed that high CAP2 expression was associated with poor prognosis of patients with glioma (P < 0.05). In Cox regression analysis, CAP2 expression was indicated as an independent prognostic factor for overall survival (hazard ratio (HR) = 1.843, 95% confidence interval (CI), 1.252-2.714; P < 0.005). CONCLUSION: CAP2 is overexpressed in glioma and it is proposed as a potential prognostic biomarker for patients with gliomas. CAP2 expression level may serve as a promising target for diagnosis and treatment of glioma.

Neurogenesis in the adult hippocampus: history, regulation, and prospective roles.

BACKGROUND: The hippocampus is one of the sites in the mammalian brain that is capable of continuously generating controversy. Adult neurogenesis is a remarkable process, and yet an intensely debatable topic in contemporary neuroscience due to its distinctiveness and conceivable impact on neural activity. The belief that neurogenesis continues through adulthood has provoked remarkable efforts to describe how newborn neurons differentiate and incorporate into the adult brain. It has also encouraged studies that investigate the consequences of inadequate neurogenesis in neuropsychiatric and neurodegenerative diseases and explore the potential role of neural progenitor cells in brain repair. The adult nervous system is not static; it is subjected to morphological and physiological alterations at various levels. This plastic mechanism guarantees that the behavioral regulation of the adult nervous system is adaptable in response to varying environmental stimuli. Three regions of the adult brain, the olfactory bulb, the hypothalamus, and the hippocampal dentate gyrus, contain new-born neurons that exhibit an essential role in the natural functional circuitry of the adult brain. Purpose/Aim: This article explores current advancements in adult hippocampal neurogenesis by presenting its history and evolution and studying its association with neural plasticity. The article also discusses the prospective roles of adult hippocampal neurogenesis and describes the intracellular, extracellular, pathological, and environmental factors involved in its regulation. Abbreviations AHN Adult hippocampal neurogenesis AKT Protein kinase B BMP Bone Morphogenic Protein BrdU Bromodeoxyuridine CNS Central nervous system DG Dentate gyrus DISC1 Disrupted-in-schizophrenia 1 FGF-2 Fibroblast Growth Factor 2 GABA Gamma-aminobutyric acid Mbd1 Methyl-CpG-binding domain protein 1 Mecp2 Methyl-CpG-binding protein 2 mTOR Mammalian target of rapamycin NSCs Neural stem cells OB Olfactory bulb; P21: cyclin-dependent kinase inhibitor 1 RBPj Recombination Signal Binding protein for Immunoglobulin Kappa J Region RMS Rostral migratory Stream SGZ Subgranular zone Shh Sonic hedgehog SOX2 SRY (sex determining region Y)-box 2 SVZ Subventricular zone Wnt3 Wingless-type mouse mammary tumor virus.

Post-traumatic stress disorder in adult victims of cluster munitions in Lebanon: a 10-year longitudinal study.

OBJECTIVE: This study aims to explore the short-term and long-term prevalence and effects of post-traumatic stress disorder (PTSD) among victims of cluster munitions. DESIGN AND SETTING: A prospective 10-year longitudinal study that took place in Lebanon. PARTICIPANTS: Two-hundred-and-forty-four Lebanese civilian victims of submunition blasts, who were injured in 2006 and were over 18 years old, were interviewed. Included were participants who had been diagnosed with PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and the PTSD Checklist - Civilian Version in 2006. Interviewees were present for the 10-year follow-up. MAIN OUTCOME MEASURES: PTSD prevalence rates of participants in 2006 and 2016 were compared. Analysis of the demographical data pertaining to the association of long-term PTSD with other variables was performed. p Values <0.05 were considered statistically significant for all analyses (95% CI). RESULTS: All the 244 civilians injured by cluster munitions in 2006 responded, and were present for long-term follow-up in 2016. The prevalence of PTSD decreased significantly from 98% to 43% after 10 years (p<0.001). A lower long-term prevalence was significantly associated with male sex (p<0.001), family support (p<0.001) and religion (p<0.001). Hospitalisation (p=0.005) and severe functional impairment (p<0.001) post-trauma were significantly associated with increased prevalence of long-term PTSD. Symptoms of negative cognition and mood were more common in the long run. In addition, job instability was the most frequent socioeconomic repercussion among the participants (88%). CONCLUSIONS: Psychological symptoms, especially PTSD, remain high in war-affected populations many years after the war; this is particularly evident for Lebanese civilians who were victimised by cluster munitions. Screening programmes and psychological interventions need to be implemented in vulnerable populations exposed to war traumas. Officials and public health advocates should consider the socioeconomic implications, and help raise awareness against the harm induced by cluster munitions and similar weaponry.

C-kit and its ligand stem cell factor: potential contribution to prostate cancer bone metastasis.

The tyrosine kinase receptor c-kit and its ligand stem cell factor (SCF) have not been explored in prostate cancer (PC) bone metastasis. Herein, we found that three human PC cell lines and bone marrow stromal cells express a membrane-bound SCF isoform and release a soluble SCF. Bone marrow stromal cells revealed strong expression of c-kit, whereas PC cells showed very low levels of the receptor or did not express it all. Using an experimental model of PC bone metastasis, we found that intraosseous bone tumors formed by otherwise c-kit-negative PC3 cells strongly expressed c-kit, as demonstrated using immunohistochemical and Western blot analyses. Subcutaneous PC3 tumors were, however, c-kit-negative. Both bone and subcutaneous PC3 tumors were positive for SCF. Immunohistochemical analysis of human specimens revealed that the expression frequency of c-kit in epithelial cells was of 5% in benign prostatic hyperplasia, 14% in primary PC, and 40% in PC bone metastases, suggesting an overall trend of increased c-kit expression in clinical PC progression. Stem cell factor expression frequency was more than 80% in all the cases. Our data suggest that the bone microenvironment up-regulates c-kit expression on PC cells, favoring their intraosseous expansion.

Prostate cancer cell-derived urokinase-type plasminogen activator contributes to intraosseous tumor growth and bone turnover.

A variety of proteases have been implicated in prostate cancer (PC) bone metastasis, but the individual contributions of these enzymes remain unclear. Urokinase-type plasminogen activator (uPA), a serine protease, can activate plasminogen and stimulate signaling events on binding its receptor uPAR. In the present study, we investigated the functional role of PC cell-associated uPA in intraosseous tumor growth and bone matrix degradation. Using a severe combined immunodeficient-human mouse model, we found that PC3 cells were the major source of uPA in the experimental bone tumor. Injection of uPA-silenced PC3 cells in bone xenografts resulted in significant reduction of bone tumor burdens and protection of trabecular bones from destruction. The suppressed tumor growth was associated with the level of uPA expression but not with its activity. An increase in the expression of PAI-1, the endogenous uPA inhibitor, was found during in vitro tumor-stromal interactions. Up-regulation of PAI-1 in bone stromal cells and preosteoclasts/osteoblasts was due to soluble factor(s) released by PC cells, and the enhanced PAI-1 expression in turn stimulated PC cell migration. Our results indicate that both tumor-derived uPA and tumor-stroma-induced PAI-1 play important roles in intraosseous metastatic PC growth through regulation of a uPA-uPAR-PAI-1 axis by autocrine/paracrine mechanisms.

Bone marrow stromal cells enhance prostate cancer cell invasion through type I collagen in an MMP-12 dependent manner.

At the cellular level, the process of bone metastasis involves many steps. Circulating cancer cells enter the marrow, proliferate, induce neovascularization, and ultimately expand into a clinically detectable, often symptomatic, metastatic deposit. Although the initial establishment and later expansion of the metastatic deposit in bone require tumor cells to possess invasive capability, the exact proteases responsible for this phenotype are not well known. The objective of our study was to take an unbiased approach to determine which proteases were expressed and functional during the initial interactions between prostate cancer cells and bone marrow stromal (BMS) cells. We found that the combination of human prostate cancer PC3 and BMS cells stimulates the invasive ability of cancer cells through type I collagen. The use of inhibitors for each of the major protease families indicated that 1 or more MMPs was/were responsible for the BMS-induced invasion. Gene profiling and semiquantitative RT-PCR analysis revealed an increased expression of several MMP genes because of PC3/BMS cell interaction. However, only MMP-12 showed an increase in protein expression. Downregulation of MMP-12 expression in PC3 cells by siRNA inhibited the enhanced invasion induced by PC3/BMS cell interaction. In vivo, MMP-12 was found to be primarily expressed by prostate cancer cells growing in bone. Our data suggest that BMS cells induce MMP-12 expression in prostate cancer cells, which results in invasive cells capable of degradation of type I collagen.