3D Hydrogel Scaffold for Characterization of Ovarian Cancer Tumor Cell Growth
Courtney Dreyer | A09795311
Jenny Pan | A97020570
Julia Wong | A09901322
Abstract
Ovarian cancer is of significant concern to women because it is both hard to diagnose and aggressive. As of current, there is a lack of viable in vitro models that accurately model ovarian cancer tumor metastasis and growth. The purpose of this research is to develop a viable 3D hydrogel that enables the ovarian cancer cell environment to be effectively modeled in vitro. The goal is to develop a 3D hydrogel scaffold that properly models the mechanical, physical, and chemical properties of the in vivo environment. These properties include but are not limited to: vascularization, cell migration, cytokine signaling, metastasis, and chemosensitivity of cancer cells. By adequately modeling ovarian cancer metastasis in vitro, the proposed scaffold will allow for more precise screening of drug efficacy prior to usage in in vivo studies. To quantify whether or not the model is accurate, mechanical, cytokine signaling, and drug efficacy tests will be carried out and evaluated to determine if the proposed 3D hydrogel scaffold is suitable as a viable in vitro representation of ovarian cancer cell environment. Thus, in the long-term, this 3D hydrogel scaffold can be used in personalized medicine and can determine the drug efficacy on a patient’s own cancer cells as a precursor to chemotherapy treatment.
Objectives and Aims
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).
Scientists have long been studying ovarian cancer and potential therapies. This includes understanding how the tumor is able to survive despite our best efforts. It's
Nanobots are invented to solve problems concerning cancer. Uncontrolled mitosis leads to cancer which have higher tendency to happen when mechanism that controls the cell is distrupted. In 2012, according to the World Health Organization, cancer is one of the leading cause of fatal. In Canada, approximately 30% of deaths are caused by cancer and abouy 191,300 new cases of cancer are expected in the year 2014. Annually, 14.1 milllon of new cases were reported while globally, there were 8.2 billion of deaths. Cancer cells need to compete with normal cells to obtain sufficient nutrient and energy for growth. Cancer cells divide out of control and are able to able to spread to other cell, tissue and organ which will result in malfunction and death.
A solid tumor is an abnormal localized multi-dimensional mass of tissue that occurs at a specific site in a solid organ such as the breast, the lung and the colon and which does not contain liquid areas [8]. Solid tumors represent the majority of human cancers [9]. Unlike Hematological diseases such as Leukemia, Basic and Clinical Researches on solid tumors are less common due to the fact that solid tumors are less sensitive to Cancer therapy than hematological malignancies [10]. Also, cells within a solid tumor do not respond equally to cancer therapy; this is due to the heterogeneity in the blood vessel distribution within a tumor and also to the difference in the proliferation rate; in fact, a solid tumor is composed of both proliferating
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Ovaries are a pair of female sex organs that store and release eggs in the process of the reproductive system. Ovarian cancer is located in the ovaries where uncontrollable multiplication of cancer cells occur (Garnick, 2014). Ovarian cancer is the fifth leading cause of death in women in the United States (Su, 2013). There are over 200,000 new cases each year worldwide and it is common in women over the age of 60 (Brain, 2014). The high mortality rate of ovarian cancer is caused by the lack of a screening techniques to detect it early on (Visintin et al, 2008). Epithelial ovarian cancer, borderline ovarian tumors, germ cell ovarian cancer, and stromal ovarian cancer are four types of ovarian cancer. There are various stages to ovarian
Undeniably, 2D monolayer cell culture method is one of the most popular models today in order to provide the first-hand information on the drug sensitivity on cell. In addition, this method is low costed and easy to be maintained [8]. But this culture method lacks the ability to mimic the tumour microenvironment such as the native extracellular matrix (ECM) of cancer cell [9]. In 2005, Zhang and his colleagues report that the cultured cells in monolayer can bring significantly difference in the rate of cell proliferation with those cell in vivo owing to the direct exposure to the oxygen and nutrient supply in monolayer culture [10]. Without the architecture of stroma, 2D monolayer model might provide inaccurate outcome due to the lack of true tumour heterogeneity in nature which consists of necrotic, quiescent and active cells [11-13]. Therefore, there is a necessity to adopt the three dimensional (3D) spheroids model first before conducting the xenograft studies as a prescreening assay to ensure a cost-effective, less time consuming and ethnically approved method in testing the sensitivity of the drug on cervical cancer cell [8].
Cancer is one of the leading causes of death today. There are a variety of different treatments for cancer such as surgical removal, chemotherapy, hormone therapy, and radiation. Chemotherapy is the most common approach it kills the cancer cells by drug toxicity or preventing cell division (Jabir et al., 2012). The issue with Chemotherapy is that it is rarely successful. The radiation approach kills cancerous cells, but it also damages the surrounding healthy cells. However, newer techniques are being developed to just attack the cancerous cells. There is a need to find a cancer treatment approach that does not kill the healthy cells along with the cancerous cells. The answer to solving this challenge lies in the successful application of
Ovarian Cancer is one of the rarest undetected cancer that begins in the ovaries, spreading through the pelvis and the belly. The ovarian cancer is about 3% of cancers among women. It causes one of the most deaths than any other cancer of the female reproductive system. It is not clear on what causes the ovarian cancer, but it can be one of the deadliest cancer of all. Females are more at risk of getting ovarian cancer as they age. Ovarian Cancer is more common in women of age 55; women who take a menopausal hormone therapy may also have a higher risk for creating ovarian cancer.
Ovarian cancer is the fifth leading cause of cancer-related deaths in females in the United States. It is anticipated that there will be about 22,280 new cases and 14,240 deaths due to ovarian cancer in 2016 [70]. Most patients present with advanced stage disease, contributing to the high death rate. Generally, these patients are treated with surgical resection followed by platinum-based chemotherapy [71]. A significant problem faced in treating these patients is the high rate of recurrence associated with platinum-resistance. Patients with platinum-resistant ovarian cancer carry a poorer prognosis with only 7-20% of them responding to subsequent therapies [72]. This reveals the urgent need for new therapeutic strategies targeted at pathways of tumorigenesis and chemotherapy resistance in the treatment of ovarian cancer.
Ovarian cancer is a disease of an uncontrolled division of abnormal cells that are in the ovaries. Ovaries produce eggs as well as hormones (estrogen, progestogen). Ovarian cancer is found in women because they have two ovaries (the size of an almond) located on each side of the ovaries (Ovarian cancer, 2000). Ovarian Cancer affects a lot of women. Statistics show that the risk of getting and dying from ovarian cancer is one in ninety-five. This cancer is the eighth most common cancer found in women. Women have a risk of one in sixty-five of getting this cancer in their lifetime. Therefore, there is a lot of research gathered that explains: the pathophysiology, clinical manifestation, and medical management.
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
Ovarian cancer is the seventh most common cancer in women, accounting for almost one-third of invasive malignancies of the female genital organs, and has remained the leading cause of death from gynecological cancers (105). Multidrug resistance (MDR) is one of the most important mechanisms, seen in various cancers, resistant to chemotherapy drugs. Overexpression of the membrane efflux proteins has a major role in the occurrence of this mechanism (106). Several members of the multidrug resistance proteins (MRPs) family, especially MRP1 and MRP2 are able to transport anticancer drugs out of the cells and present in many different types of tumors, and therefore assumed to cause MDR (107).
The importance of extracellular matrix (ECM) composition, stiffness, 3D architecture and its influence cell proliferation, differentiation, migration and survival have been well characterized(Jansen et al., 2015) (Kourouklis, Kaylan, & Underhill, 2016; Yang et al., 2016) (Coombs, Leonard, Rush, Santistevan, & Hedberg-Dirk, 2016; Rammensee, Kang, Georgiou, Kumar, & Schaffer, 2016; Subbiah et al., 2016).Cells can sense discreet changes in ECM make-up, and have been shown to behave differently in a 2D in vitro setting compared to in 3D in vitro culture (Alessandri et al., 2014; Lu et al., 2013). While the precise mechanism remains to be defined, the tumor stiffness has been implicated as a potential initiator of metastasis and tumor progression (Fenner et al., 2014). The reorganization of structural components of tumors has been shown to enhance both tumor formation and metastasis, demonstrating a structural link between density, the stromal component, and the tumor (Chaudhuri et al., 2014). Furthermore, epithelial cells are known to respond to changes in environmental stiffness enhancing proliferation and cell motility (Chaudhuri et al., 2014). The composition of the architecture of tumors differs from that of normal tissue both in molecular makeup and mechanical properties (rigidity and tensile forces) (Hansen & Bissell, 2000)Tumor cells will react to changes in architecture leading to
Reduction in macrophage infiltration, lead to concomitant decrease in circulating cancer cells. In addition, the EGF–CSF paracrine loop is also important for intravasation, as blocking either signaling pathway lead to a significant reduction in the number of blood-borne cancer cells. Cancer cells and macrophages also use collagen fibres as tram lines to rapidly travel through the stroma. Many of these fibres are tethered to blood vessels, resulting in cancer cells accumulating at these vessels. The density of these fibres is regulated by macrophages, at least during development. (Joyce & Pollard, 2009), (Hanahan & Weinberg, 2011)