Evidence For Pro Metastatic Role Of Tams : Genetic Studies

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).

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,

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.

Distant spread of primary malignant cells to local and distant sites was explained by several models. Cumulative research shows a pivotal role of tumor microenvironment in the process of malignant cell dissemination. This role occurs through angiogenesis and epithelial-stromal interactions, via the paracrine secretion of growth factors by stromal cells, which induce an epithelial-mesenchymal transition in neighboring epithelial cells. This result in the increased migration of epithelial cells [3].

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

Multiple myeloma accounts for about 0.8 % of all the cancers and around 63,000 people are reported to die from it every year. The exact etiology of MM is not clearly understood45. BMPs are potent inhibitors of multiple myeloma cells and are found in the bone marrow where these cells reside. Multiple myeloma cells are able to grow and continue proliferation within the bone marrow microenvironment. It is therefore important to understand how myeloma cells are able to escape the tumor suppressing activity of BMPs. A more in-depth knowledge in this could lead to development of new treatment and better targets for MM.

Breast tissue is comprised of a basement membrane and epithelial cells which are located within an adipose and mesenchymal stroma (RO). The stroma consists of a diverse range of cells including endothelial cells, leukocytes, fibroblasts and many others (Polyak, 2007). The extracellular matrix (ECM) is a major component of the cancer microenvironment or niche consisting of collagen, laminin, fibronectin, proteoglycans and growth factors, including HER2 (Yoneda et al., 2012)(Reference). Invasive carcinomas unlike non-invasive carcinomas extend into the surrounding ECM and tend to induce modifications in the adjacent stroma (LR) (Fernandez-Vega et al., 2013).

(2000) reported that 90% of IBC tumours displayed an over expression of RhoC GTPase, an oncogene that contributes to the invasive nature of IBC. Rho protein activation causes the actin-myosin contractile filaments and focal adhesion complexes to assemble, leading to the formation of lamellipodia. Lamellipodia form at the edge of cells and drive cell migration and motility, furthering metastasis in IBC (Machesky 2008).

target organ of metastases originating from lung cancer (40-50%), breast cancer (15-25%) and melanoma (5-20%),

Tamoxifin selectively and competitively bind/block estrogen receptor resulting in inhibition of estrogen mediated gene expression and proliferation thereby suppressing growth of tumor in breast tissues. Although Tamoxifen is highly efficient in its performance but recently it has been demonstrated that patients with all stages of ER positive breast cancer become immune to Tamoxifen under prolonged Tamoxifen treatment. The mechanism of this resistance is still not clear however; recently workers have demonstrated that Tamoxifen effect is overridden by increase in other growth factor signaling pathways. This Tamoxifen override can be rescued by inhibiting growth factor signaling pathways. Cumulative clinical studies suggests that the most common growth factors associated with Tamoxifen resistance include overexpression of EGFR, HER-2, and elevated levels of Akt or ERK in few cases if not all. In vivo studies have shown overexpression of HER-2 in 10% of Tamoxifen treated ER positive breast cancers, one mechanism of Tamoxifin resistance where Tamoxifen acts as estrogen and activates HER-2 which in turn phosphorylates ER and A1B1 (SRC3) protein, leading to proliferation of cells. Stress and/or signaling pathways also contribute to Tamoxifen resistance. Studies support the hypothesis that phosphorylated members of jun N-terminal kinase (JNK) and mitogen- activated protein kinase (MAPK) also contribute to Tamoxifen

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

The uncontrollable spread of cancer is the principal event which leads to the death in individuals with cancer and it is the greatest barrier of developing cures for cancer. Metastasis is the progressive spread of malignant cancer cells from the primary tumour to secondary organ in distant sites and this potential is dependent on the specific microenvironment which support them to complete each step of the metastatic process (Poste & Fidler 1980). To understand the molecular basis of metastasis, investigators have now separated the complex and highly selective metastasis process into series of steps to try and solve the problems cause by

Background: The issue of breast cancer affecting many individuals is a growing one. At the present time period it is now found that one in every eight women will be told they have breast cancer (“National Breast Cancer Foundation”, 2012). Therefore there is a significant amount of research going into this area. In addition, to the large amount of women and smaller amount of men who will be potentially diagnosed with breast cancer has become a global burden because those with metastatic cancer will eventually have cancer cells travel to other parts of their body (“National Breast Cancer Foundation”, 2012). MCF-7 cells are commonly used to study the mechanism of action and how the tumor works for human breast cancer (Osborn, Trent& Hobbs, n.d.). These types of cells are the most common in laboratories for cancer research. According to C. Osborn MCF-7 cells are used because they typically “demonstrate similar morphology”, however the chromosomal structures can be different. Thus leading to varied results. In addition, Osborn states that MCF-7 cell lines will usually have estrogen receptors, and progesterone receptors. The amounts of estrogen and progesterone receptors can affect the proliferation of the cells. (Osborn, Trent, & Hobbs, n.d.). Therefore, the experiment will be using cells taken from a sixty nine year old patient with metastatic cancer.