Metastasis is an extraordinarily complex process. A sequence of steps is executed by a cancer cell to successfully form distant colonies at a secondary site. Typically, cancer cells escape from the primary tumour, break through basement membrane and invade surrounding tissues, encounter the circulatory system and/or lymphatics and travel to distant sites. Finally, they are arrested in small capillaries while being able to grow and form new tumours.[1] Tumour cells acting through this multistep metastatic cascade need to acquire some communicational skills and for that reason they seem to have numerous interactions with the extracellular matrix (ECM).
Matrix metalloproteinases (MMPs) comprise a family of proteolytic enzymes that possess the capability to control ECM remodelling and degradation, both being active events in tumour invasion. Consequently, their expression and activity have been extensively studied in various human cancers. [2] Furthermore, enhanced MMP expression and activity imply poor prognosis and risk of recurrence. [3] Hence, MMPs have been considered as promising therapeutic targets for cancer following the discovery through which their aberrant up-regulation was proved to be engaged in cancer cell invasion and motility.
MMPs group is comprised of 24 enzymes that have been identified to degrade ECM and basement membrane as well as release of bioactive molecules. However, individual MMPs have been found to have pro-metastatic as well as anti-metastatic
Cancer, medically called ‘tumorigenesis’ (Thaker, Lutgendorf, & Sood, 2007, p.430) occurs when cells in the body orient themselves for malignant growth. Such cells show ‘self-sufficiency in growth signals’, are ‘insensitive to anti-growth signals’ and have ‘limitless replicative potential’ (Thaker, Lutgendorf, & Sood, 2007, p.430). Once a particular set of cells become malignant, the malignancy can spread to other set of cells in different organs due to ‘crosstalk’ between the affected cells and their surrounding ‘tissues’ and ‘micro-environments’(Thaker, Lutgendorf, & Sood, 2007, p.430).
Aim 2: To identify the proteins in the exosome of the metastatic cancer cells. The exosome or the secretory vesicle fraction will be concentrated from the extracellular media of metastatic, non-metastatic cancer cell and compare with the control cells. SILAC labelled proteomic analysis will be performed in the isolated exosomes to identify the proteins that are specific in metastatic cells.
Cancer is listed as the second most common cause of death in western countries; particularly, in adults. Though it has a long antiquity, its prevalence and incidence today is pervasive and the war on cancer has not been promising. Malignant neoplasia is characterized by uncontrolled growth and the ability to metastasize or spread from the original site. Cancer results from mutations that promote cell proliferation and inhibit cell adhesion (metastasis). According to the National Cancer Institute (2016), “Cancer can also spread regionally,
Even though they did not discover the precise mechanisms engaged, the investigators think the makeup of the NETs allows cancer cells migrate via tissue by literally consuming through the protein-scaffolding that forms the tissue framework. They recommend the NETs develop small gaps and crevices for the cancer cells, thus assisting to promote new colonies away from the primary tumor.
such examples include IL1, IL6, IL10, PGE2, TGF-β, VGEF, MCSF, MIF & GM-CSF (Saskia J. A. M. Santegoets, 2016). VEGF exerts a variety of effects on vascular endothelial cells which promotes the formation and growth of new blood vessels. VEGF induces calcium transients, which causes stimulation of endothelial cells, which leads them to migrate and divide. Tumour cells are also capable of ‘shedding’ alarm proteins, such as MHC-1 complex, which as a result can have a dampening effect on NKG2D mediated activation of T cells/NK cells (Saskia J. A. M. Santegoets, 2016). As chemokines, matrix metalloproteases (MMP’s), DNA, RNA and exosomes are all highly soluble, they can not only operate within the tumour microenvironment (TME), but can enter the circulation, and subsequently effect distant mediators, such as bone marrow or lymph nodes, which can in turn suppress immune response.
By secreting this protein, VEGF receptors in the vasculature then activate the extracellular kinase and mitogen-activated protein (MAP) kinase signal transduction pathway. This induces proteins that breakdown the blood vessels basement membrane, allowing endothelial cells to invade. The breakdown of the membrane allows fluid and proteins to escape through the vasculature. One of these proteins, matrix metalloproteinase (MMP), breaks down the extracellular matrix between the tumour and blood vessel and allows the VEGF to stimulate receptors on the new endothelial cells. This causes proliferation of the endothelial cells, tube formation and migration towards the area signalling VEGF (the tumour cells), allowing the growth of new blood vessels into the tumour. (Spyridopoulos, I. 2002).
Signaling pathways that result in cell migration are often useful in understanding how cancer cells metastasize. The researchers of Swaminathan et al., 2016 examine how adhesion site assembly occurs while Nader et al., 2016 focuses primarily on the adhesion turnover both are fundamental processes in cell migration. Integrins play a dominant role in nascent integrin-mediated adhesions (NAs) which are important in lamellipodium protrusion and generating traction at focal adhesion points involved in cell motility. Integrins have been extensively studied and are linked to wound healing as well as metastasis in cancer cells (Lawson et al., 2012). When extracellular signals, either chemical or physical, contact the cell surface it triggers a response that induces movement. If the signaling molecule is a growth factor (ex. Epidermal Growth Factor) it could activate a GTPase protein coupled receptor (GPCR). The next is a signal cascade often led by Rabs or Ras (small G-proteins) proteins that are powered by GTPase hydrolysis, which often recruits and activates Wiskott–Aldrich Syndrome protein (WASP) or Scar. Previous studies identified cancer cell that use Rab-coupling to control cell motility by regulating B-intgrins trafficking (Nader et al., 2016). WASP recruits Actin related protein 2 and 3 (Arp2/3) complex to the cell membrane and activates it
MMP-9 is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracellular matrix and have an important role in cancer progression. VEGF is a protein produced by cells that stimulates angiogenesis. It restores the oxygen supply to cells when blood circulation is inadequate and also similar to MMP-9 causes to cancer
Distant metastases are mostly identified in patients of osteosarcoma with the estimation of about 85% after surgery. Mostly they occur in lungs however it may also metastasizes to soft tissues and other different bone. Osteosarcoma is lethal because of pulmonary metastasis with widespread progression that leads to respiratory failure. Tumor metastasis and invasion are multistep complex process in which tumor cells alter cell–extracellular matrix (ECM) associations at the primary tumor site to invade adjacent tissues and thus translocated through the vascular vessels to other systems to form secondary tumors there. MMPs are family of proteolytic enzyme that plays an essential role in tumor metastasis and invasion by breaking the ECM and basement
Further studies have to be conducted to explain the role of BMPR2 in MM. One possible option is to generate stable transduced myeloma cell lines with over expressed BMPR2. This will help understand role of BMPR2 with BMPs much better. It would be helpful to find out the effects of BMPs and the role of BMPR2 in various other cancer cell lines and not just in MM.
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Cancer metastasis in the main character and hallmark of cancer progression [6]. Metastasis is a multi-step process beginning from detachments of cancer cells from the primary tumor, disruption of the basement membrane for invading to surrounding tissue. Subsequently, the cancer cells able entry to the blood and lymphatic system to spread into other part of the body and extravasation for growth and proliferate in distant sites [7]. Matrix metalloproteinase (MMP) is a zinc-dependent endopeptidase which responsible in degradation the component of extracellular matrix (ECM) proteins including collagen, elastin, fibronectin. MMP can secrete by inflammatory cells, osteoblast, fibroblast, and also cancer cells. MMP has a pivotal role in promoting
Cancer is one of the leading causes of death worldwide as it can develop in almost any organ or tissue. Significant advances in understanding the cellular basis of cancer and the underlying biological mechanisms of tumour has been vastly improved in the recent years (Jiang et al. 1994). Cancer is a genetic disease which requires a series of mutation during mitosis to develop, its characteristics can be associated with their ability to grow and divide abnormal cells uncontrollable while in the mean time invade and cause nearby blood vessels to serve its need. Even though many people are affected by cancer today, the abilities which cancer cells have make it hard to find a single effective treatment for cancer. The focus of research now lies
When HL-60 cells are treated with PMA they differentiate into monocytes and when HL-60 cells are treated with DMSO they mainly differentiate into granulocytes. Monocytes and granulocytes are both a part of the immune system, meaning the human body uses them to fight foreign invaders, and have some similarities that help signify commonalities in their functions as white blood cells; however, they also have some differences that highlight their distinct characteristics that allow them to attack unwelcome intruders in their own unique ways. One of the similarities between monocytes and granulocytes is that they both produce matrix metallopeptidase 2, or MMP-2, but one of the differences between these two cell types is that only monocytes produce matrix metallopeptidase 9, or MMP-9. Matrix metalloproteinases, such as MMP-9 and MMP-2, break down proteins in the extracellular matrix allowing cells to move from one place to another. The ability to move is somewhat important for granulocytes, which move a to an intruder and explode to fight off infection, but the ability to move is vitally important for monocytes, which move to areas of infection and digest the pathogens and then move
Epithelial cells (ECs) are the structural unit of epithelium, a tissue type that is responsible for lining the inner and outer surfaces of the body, as well as formation of many glands, including endocrine, exocrine, serous, mucous, and sebaceous. ECs are polarized, with the apical surface facing the lumen and the basal surface anchoring to a specialized extracellular matrix (ECM) layer, known as the basal lamina which separates epithelial cell from underlying tissues. To maintain the physical and functional integrity of the epithelium, ECs are also laterally linked to one another through cell-to-cell adhesion molecules (CAM), most importantly, members of the cadherin family. As a result, ECs within an ordinary epithelium have very limited mobility. Nevertheless, non-pathological epithelial plasticity does occur, for example, in neurulation – an important morphogenetic movement during embryogenesis. In these circumstances, ECs tend to move in group and the integrity of the whole layer is not compromised.