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Factors affecting tumor invasion

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Factors affecting tumor invasion

Supervisor Dr. eman elhewady

Students :
• Mahmoud abd-elazeem 873 • Mahmoud emad-eldeen 875 • Mahmoud anter sheble 876 • Mahmoud mohamed arafa 879 • Mahmoud mohamed mohamed 880 • Mahmoud mostafa fakhry 881

Contents
Introduction:


• •

tumor (definition) Benign / malignant Malignant (invasion –metastases) Invasion (definition)

Factors affecting tumor invasion:
• • • • • • • • • • Angiogenesis The lymphatic vasculature Cell motility Growth factor Integrins Expression EGFR (The epidermal growth factor receptor) MMPs ( matrix metalloproteinases) Tobacco Endostar MRI- CT

References.

Introduction
Tumour definition:
An abnormal growth of tissue resulting from uncontrolled, progressive multiplication of cells and serving no physiological function.

There are two types of tumour: Benign tumor
benign tumor is basically a tumor that doesn't come back and doesn't spread to other parts of the body. A tumor is a mass of tissue that serves no useful purpose and generally exists at the expense of healthy tissues. Benign tumors tend to grow more slowly than malignant tumors and are less likely to cause health problems.

Malignant tumor(cancer)
malignant tumors grow faster than benign tumors and are more likely to cause health problems. it can invade and spreed to other parts of body by two procceses that called invasion and metastasis.

Invasion:
Tumor invasion is a multistage process in which cellular motility is associated with controlled proteolysis and that involves interactions between tumor cells and the ECM. During this process, malignantly transformed cells detach from the primary tumor, migrate, and cross structural barriers, including basement membranes and surrounding stromal collagenous ECM. Degradation of stromal ECM is also considered essential in tumor-induced angiogenesis.

Metastasis:
The process by which cancer spreads from the place at which it first arose as a primary tumor to distant locations in the body.

Basic components of the tumors : All tumors, benign and malignant, have two basic components: (1) proliferating neoplastic cells that constitute their parenchyma . (2) supportive stroma made up of connective tissue and blood vessels. Although parenchymal cells represent the proliferating "cutting edge" of neoplasms and so determine their behavior and pathologic consequences, the growth and evolution of neoplasms are critically dependent on their stroma. The progression of a tumour from one of benign and delimited growth to one that is invasive and metastatic is the major cause of poor clinical outcome in cancer patients. Tumor invasion and metastasis formation are major obstacles for successful cancer therapy. The invasion and metastasis of tumours is a highly complex and multistep process that requires a tumour cell to modulate its ability to adhere, degrade the surrounding extracellular matrix, migrate, proliferate at a secondary site and stimulate angiogenesis. Knowledge of the process has greatly increased and this has resulted in the identification of a number of molecules that are fundamental to the process. The involvement of these molecules has been shown to relate not only to the survival and proliferation of the tumour cell but, also to the processes of tumour cell adhesion, migration, and the tumour cells ability to degrade and escape the primary site as well as play a role in angiogenesis. These molecules may provide important therapeutic targets that represent the ability to target specific steps in the

process of invasion and metastasis and provide additional therapies. Angiogenesis and lymphangiogenesis the development of new blood vessels and lymphatics from the pre-existing vasculature, respectively are processes with integral roles in embryonic development and numerous diseases, including cancer progression and metastasis and inflammation. Tumor cells near pre-existing blood vessels secrete growth factors and chemokines such as VEGF-A ( vascular endothelial growth factor A ), bFGF ( basic fibroblast growth factor ), and TNFα ( tumour necrosis factor alpha ) that stimulate quiescent vascular endothelium to enter the cell cycle. Angiogenesis is the better understood of the two processes, in part due to the intense research focus placed upon the field because of the significance of blood vascular development for tumor growth and ischemic disease.

the process of new blood vessel formation from pre-existing ones, plays a key role in various physiological and pathological conditions, including embryonic development, wound repair, inflammation, and tumor growth. The nascent vascular bed expands by sprouting and matures into a system of stable vessels. Hypoxia is an important stimulus for expansion of the vascular bed. Initially, cells are oxygenated by simple diffusion of oxygen, but when tissues grow beyond the limit of oxygen diffusion, hypoxia triggers vessel growth by signaling through hypoxia-inducible transcription factors (HIFs (HIFS))upregulate many angiogenic genes, include the gene for Vascular Endothelial Growth Factor (VEGF-A). VEGF-A can bind the receptors VEGFR-1 and VEGFR-2 to induce endothelial cell migration, proliferation, and survival.

Factors affecting tumor invasion: • Angiogenesis :

VEGF-A stimulates physiological and pathological angiogenesis and is therefore currently being evaluated for pro- and anti-angiogenic therapy. To induce angiogenesis, many angiogenic growth factors, including basic fibroblast growth factor (FGF-2)interact with signaling receptors expressed on the endothelial cell (EC) surface that, with some exceptions such as TNF and chemokine receptors, are endowed with tyrosine kinase (TK) activity. Additionally, many angiogenic growth factors are also engaged in multiple interactions in the extracellular environment and on the EC surface. For instance, angiogenic growth factors bind a variety of free or immobilized proteins, polysaccharides, and complex lipids present in the extracellular environment that may affect their integrity, stability, bioavailability, and diffusion. Angiogenesis not only depends on the expression of specific growth factors such as vascular endothelial growth factor and fibroblast growth factor, but also on cell adhesion to the extracellular matrix (ECM). During growth of new blood vessels, adhesion to the ECM via integrins regulates proliferation, survival, and motility of endothelial cells.

The lymphatic vasculature:

performs a crucial function by transporting fluid and macromolecules, including fat, from tissues back to the blood circulation. It also links tissue fluids to lymph nodes as an immune surveillance system. A lack of molecular markers specific to the lymphatic system has been an impediment to lymphangiogenesis research until recently, when the identification of several such markers, Lyve1( lymphatic veaael endothelial receptor 1), Prox-1, and Podoplanin, has led to molecular insights into lymphangiogenesis. Numerous pathologies are associated with the lymphatics, such as the metastatic spread of

cancer, lymphangiomas, lymphangiectasias, and lymphedema. Therapeutic strategies based upon the expanding body of lymphatic knowledge are now being considered. Metastatic tumor cells can exploit the lymphatic vasculature, as they frequently spread through the lymphatic vessels and colonize lymph nodes. In particular, breast cancer and melanoma are known to spread to lymph nodes, necessitating radical surgery that destroys the lymphatic vessel network and leads to impairment of afferent lymphatic flow. Many patients who undergo radical axillary lymph node dissection subsequently develop lymphedema. Clinically, lymphedema presents as visible or palpable tissue swelling. Breast cancer (BC)-related lymphedema is a chronic condition that diminishes quality of life and contributes to impairments in limb range of motion, loss of strength, and functional limitations with activities, such as lifting and reaching. Growth factors capable of directly inducing the growth of lymphatic vessels have been characterized. These factors, VEGF-C and VEGF-D, are ligands for the endothelial cellspecific tyrosine kinase receptors VEGFR-2 and VEGFR-3.8 VEGFR-2 is thought to be the principal mediator of angiogenesis, whereas VEGFR-3 is crucial for development and growth of lymphatic and blood vessels. Cell motility is one of the defining characteristics of invasive tumors, enabling tumors to migrate into adjacent tissues or transmigrate limiting basement membranes and extracellular matrices. Invasive tumor cells have been demonstrated to present dysregulated cell motility in response to extracellular signals from growth factors and cytokines. Recent findings suggest that this growth factor receptor-mediated motility is one of the most common aberrations in tumor cells leading to invasiveness and represents a cellular behavior distinct from-adhesion-

Cell motility:

related haptokinetic and haptotactic migration. Cell motility is mainly affected by growth factor-induced cell motility and tumor cell invasiveness, and the implications for development of targeted agents, with particular emphasis on signaling from the epidermal growth factor (EGF) and hepatocyte growth factor (HGF) receptors, as these have most often been associated with tumor invasion. The nascent models highlight the roles of various intracellular signaling pathways including phospholipase C-gamma (PLC gamma), phosphatidylinositol (PI)3'-kinase, mitogenactivated protein (MAP) kinase, and actin cytoskeletonrelated events.

Many cancer cells develop growth self-sufficiency by acquiring the ability to synthesize the same growth factors to which they are responsive. The protooncogene SIS, which encodes the chain of platelet-derived growth factor (PDGF), is overproduced in many tumors, especially lowgrade astrocytomas and osteosarcomas. Furthermore, it appears that the same tumors also express receptors for PDGF and are hence responsive to autocrine stimulation. Although an autocrine loop is considered to be an important element in the pathogenesis of several tumors, in most instances the growth factor gene itself is not altered or mutated. More commonly, products of other oncogenes such as RAS (that lie along many signal transduction pathways) cause overexpression of growth factor genes, thus forcing the cells to secrete large amounts of growth factors, such as transforming growth factor- (TGF-). This growth factor is related to epidermal growth factor (EGF) and induces proliferation by binding to the EGF receptor. TGF-is often Subcellular localization and functions of major classes of cancer-associated genes. The protooncogenes are colored red, cancer suppressor genes blue, DNA repair genes green, and genes that regulate apoptosis purple. Integrins Expression:

Growth Factors:

Integrins are a family of heterodimeric transmembrane glycoproteins mediating cell–cell and cell–ECM connections. The integrin family consists of eight β and 18 α subunits that assemble as heterodimers to form 24 distinct integrins15. The main ligands for integrins in the extracellular space are extracellular matrix proteins, such as laminin and collagen, as well as cellular counter-receptors. Integrins are linked to the cytoskeleton through their cytoplasmic domains. Integrins modulate the cytoskeleton via various submembrane adaptor proteins and kinases.16 Integrins transduce signals across the plasma membrane in both directions; integrin binding to its ligands requires its activation by inside-out signals. Conversely, integrin ligation triggers outside-in signals that regulate different aspects of cell behavior, including cell survival, control of transcription, cell proliferation, cell motility, and cytoskeletal organization. Cell migration and invasion are crucial processes in a variety of physiological and pathological conditions. They have been identified as prerequisites for reproduction, growth, and development. In addition, migration and invasion perform critical functions not only in normal homeostasis including proper wound healing and immune system function but also in pathological conditions including tumor progression via angiogenesis and metastasis. These processes are controlled by a variety of internal and external signals via complex signal transduction cascades. A variety of molecules in focal adhesions and the actin cytoskeleton are involved in cell migration in a coordinated manner. For the process of cell migration, the assembly and disassembly of cell adhesion sites occur simultaneously at both the front and rear edge of a cell. The invasion process requires the proteolytic degradation of the ECM by several proteases, including matrix metalloproteinases (MMPs), plasminogen activators, and serine proteases.

Because integrins serve as transmembrane linkers between their extracellular ligands and the cytoskeleton, they have the capacity to influence cell migration during embryogenesis, angiogenesis, wound healing, immune and nonimmune defense mechanisms, hemostasis, and oncogenic transformation. Therapeutic Applications: Preclinical studies have suggested that antagonists of several integrins might be useful to suppress tumor angiogenesis and growth, either alone or in combination with current cancer therapeutics. Of the several integrin antagonists undergoing clinical evaluation for cancer treatment, all have proven nontoxic, reduced angiogenesis and tumor growth in human melanoma xenografts in nude mice and rats, most carcinoma cells express integrin αvβ5, which has been shown to promote tumor cell invasion. Targeting the alpha v integrins may thus block both tumor cell invasion and metastasis and tumor angiogenesis.

autocrine pathway plays a crucial role in human cancer since it contributes to a number of highly relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. Tumor-induced angiogenesis is well known as a key player in sustaining local tumor growth, invasion and metastatic spread. In cancer cells the EGFR autocrine pathway controls, in part, the production of several proangiogenic growth factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The link between EGFR and VEGF signaling is also testified by the major anticancer effect due to one of EGFR by selective anti-EGFR agents of tumor-induced, VEGF-mediated angiogenesis . In cancer cells, altered control of angiogenesis could be a

EGFR (The epidermal growth factor receptor):

mechanism responsible for resistance to EGFR inhibitors in vivo, as it has been shown in preclinical models with antiEGFR blocking MAbs (monoclonal antibodies). Among a variety of approaches used to target EGFR signaling, EGFR blocking monoclonal antibodies and small molecular weight EGFR tyrosine kinase compounds have been successfully developed. The results of a large body of preclinical studies and clinical trials suggest that targeting the EGFR could represent a significant contribution to cancer therapy. Both types of agent exert a significant antiproliferative activity when used alone or in combination with conventional antitumor treatments, such as chemotherapy or radiation therapy. Although the advanced clinical development of EGFR blocking drugs demonstrates their efficacy in some human metastatic diseases, such as lung, head and neck and colorectal cancers, the issue of constitutive resistance in a large number of patients and the development of acquired resistance in the responders remains an unexplored subject of investigation. Recent evidence suggests the role of specific activating mutations within the tyrosine kinase domain of EGFR to explain the dramatic responses to small molecule tyrosine kinase inhibitors in a subgroup of lung cancer patients. However, the intrinsic molecular mechanisms of resistance to these drugs are still unclear. belong to a family of structurally related proteolytic enzymes that mediate degradation of the extracellular matrix and the basement of membranes. High levels of MMP activity have been linked to tumor growth, invasion, and angiogenesis inflammation and may even work in a nonproteolytic manner. The tissue inhibitor of metalloproteinases family, including TIMP-1, 2, 3, and 4, regulates the activity of multifunctional metalloproteinases. Among TIMP members, TIMP-2 is most frequently

• MMPs ( matrix metalloproteinases)

investigated because it is a unique member of the TIMP family and involved in cancer progression and metastasis. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. Inflammatory conditions can initiate or promote oncogenic transformation and genetic and epigenetic changes in malignant cells. An inflammatory microenvironment further supports tumor progression. Cancer-associated inflammation is marked by the presence of specific inflammatory cells and inflammatory mediators, including cytokines and chemokines. Nuclear factor-κB (NF-κB) transcription factor plays an essential role in innate and adaptive immune responses, cell proliferation, apoptosis, and tumorigenesis. Constitutive activation of NF-κB has been directly implicated in tumorigenesis of various cancer types. Recent evidence also suggests a crucial role for signal transducer and activator of transcription (STAT) family in selectively inducing and maintaining a procarcinogenic inflammatory microenvironment, both at the initiation of malignant transformation and during cancer progression. The targeting of inflammatory mediators (chemokines and cytokines, such as TNF-α and IL-1β), key transcription factors involved in inflammation such as( NF-κB and STAT), or inflammatory cells decreases the incidence and spread of cancer. Therefore, anti-inflammation is an essential strategy for the cancer therapy.

Mounting evidence indicates that cigarette smoking not only promotes tumorigenesis but also may increase the spread of cancer cells in the body. However, the intracellular mechanisms by which cigarette smoking promotes metastasis of human lung cancer remains enigmatic. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)1-butanone (NNK) is an important component in cigarette smoke and is formed by nitrosation of nicotine. mu- and

Tobacco

m-calpain (calpain I and calpain II) are major members of the calpain family, which are ubiquitously expressed in both small cell lung cancer and non-small cell lung cancer cells. researches indicated that NNK (nicotine-derived nitrosamine ketone) potently induces phosphorylation of both mu- and m-calpain in association with their activation and increased migration as well as invasion of lung cancer cells. Treatment of cells by blocking phosphorylation of mand mu-calpain and resulted in suppression of NNK-induced cell migration and invasion.

a novel recombinant human endostatin expressed and purified in Escherichia coli with an additional nine-amino acid sequence forming another his-tag structure, was approved by the State Food and Drug Administration of China (SFDA) in 2005 for the treatment of non-small-cell lung cancer. However, the molecular mechanism of its potent anticancer activity remains poorly understood and warrants further investigations. In this study, we examined the anti-invasive activities of endostar in vitro. The results showed that endostar suppressed MDA-MB-435 cell adhesion to the fibronectin-coated substrate in a concentration-dependent manner. It could inhibit the wound healing migration of MDA-MB-435 cells and invasion of MDA-MB-435 cells through reconstituted ECM (matrigel). Zymography revealed that endostar decreased the secretion of MMP-2 and MMP-9. Endostar could also inhibit the expressions of MMP-2 and MMP-9 in MDA-MB-435 cells. Additionally, endostar exerted an inhibitory effect on the phosphorylation of ERK1/2. Collectively, these data provided a molecular basis for the anti-invasive effects of endostar.

Endostar

The processes of tumor invasion and metastasis have been well characterized at the molecular level, and numerous biomarkers of tumor aggressiveness have been discovered.

• MRI- CT

Molecular imaging offers the opportunity to depict specific cell markers relevant to tumor aggressiveness. Targetspecific molecular imaging probes for tumor invasiveness have been developed for positron emission tomography and optical imaging, but progress in MRI has been slower. For example, proteases associated with tumor invasion, such as specific matrix metalloproteinases or cathepsins, can be targeted in vivo using optical and positron emission tomography methods, but have not yet been successful with MRI. -Worldwide, cervical cancer is the second most common malignancy in women, and is a major cause of morbidity and mortality. Accurate tumor staging is essential for optimal treatment planning and prognosis. Cervical cancer is staged by clinical examination according to the International Federation of Gynecology and Obstetrics staging system. However, clinical staging has inherent deficiencies in evaluating several parameters that are critical for treatment planning. It is now widely accepted that cross-sectional imaging, and in particular MRI, has an important role to play in the staging of these tumors. MRI is an excellent modality for depicting invasive cervical cancer: it can provide objective measurement of tumor size and provides a high negative predictive value for parametrial invasion. MRI and positron emission tomography (PET)/computed tomography (CT) play key roles in identifying recurrent disease. Many studies have shown that cancer cell differentiation and microvascular invasion play a principle role in cancer progression and metastasis, and non-invasive imaging techniques such as CT, MRI and US assessing the differentiation and the surgical resectibility and the prognosis of cancers are now of great importance. This study aimed to explore the correlation of triple-phase multi-slice CT scan with the histological differentiation and intratumor microvascular/lymphatic invasion of progressive gastric cancer.

• METHODS

A present study included 64 patients with gastric cancer, all of whom underwent routinal and dual-phase contrast enhancement multi-slice CT examinations of the upper abdomen before surgery. The post-operative specimens were used for determination of histological differentiation, cancer cell invasion of intratumoral microvascular/lymphatic vessel identified by CD34 and D240 expression. Correlations between contrast enhancement ratio (CER) of triple-phase multi-slice CT scan in gastric cancer and histological differentiation as well as intratumoral microvascular/lymphatic invasion were compared and analyzed.

• CONCLUSIONS
CER of triple-phase multi-slice CT scan in gastric cancer is closely correlated with intratumoral microvascular and lymphatic invasion, and also could be used as a marker for histological differentiation.

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