Tumor Recruitment And Reprogramming ( R & R ) Of Bystander Cells

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).

Some have argued that important information related to the way in which, and the rapidity in which, cancer cells metastases has been obtained by this study. But this has been highly debated (Standler, 1997).

Mikala Egeblad used live-imaging technology to evaluate how cancer cells hijack NETs to enhance their capability to propagate. They applied a mouse model of triple-negative breast cancer - a cancer well-known to be most aggressive in human beings, and notorious for distributing and relapsing. The authors note in their paper:

When cells were treated with NS-398 (suppresses COX2 activity), bystander spread to neighboring cells were drastically reduced (Zhou et al., 2005). The spread of irradiated tumor cells to normal cells is dependent on the coupling strength of the GJC and/or the permeability. The effects of COX2 being coexpressed with either Cx32 or Cx26 showed contrasting results. With the induced expression of Cx26, propagation of radiation damage to neighboring DNA can be seen (figure (1,2)). On the contrary, the expression of Cx32 helped reduce the spread through bystander effect (Zhao, de Toledo, Hu, Hei, & Azzam, 2014). Since different subtypes of connexins have a different permeability to signaling molecules, Cx32 may have a lower permeability to different secondary messengers. In cells expressing COX2 knockdown, the coupling of Cx26 to AG1522 cells (bystander human fibroblasts) were drastically delayed (delay of bystander effect) (Zhao et al., 2014). Thus, it may present clues to pathways regulating GJIC in radiotherapy

The third step is metastasis. Which is the invasion of cancerous cells into nearby tissues as well as the migration of cancerous cells to other tissues via

Background and Rationale. Pancreatic ductal adenocarcinoma (PDAC) is highly malignant with the lowest survival of any human cancer (1). Extensive metastasis and therapeutic resistance are the two major contributors to the dismal prognosis of this malignancy (3-5). The mechanisms by which PDAC cells can successfully spread and metastasize are largely unknown, and molecular events underlying the tumor cell’s resistance to therapeutics remain to be defined (6,7). The objective of this proposal is to use a special type of cancer cell, circulating tumor cell (CTC), responsible for the poor prognosis to characterize these cells and to test therapeutics we have designed to overcome therapeutic resistance and improve patient survival.

As such, it is important for the new doctor and patient to identify the poorly differentiated cancer cells that have the potential of spreading fast. This early recognition of this type of

Stem cells are a growing phenomenon in the cancer research world. Researchers are getting closer and closer to a cure, they are exploring other options to treat cancer. Stem cells are relatively new to the medical world, making their first appearance in 1956 (”Timeline for Stem Cell Research”, 1), and as with everything, there are flaws. Despite these flaws, stem cell treatment is something more people are turning to, as it is widely becoming one of the most popular ways to treat cancer (besides radiation and chemotherapy, respectively). Stem cell treatments are not accepted by all, as the rising questions are becoming, ‘Do stem cells worsen cancer?’, or better yet ‘Can stem cell treatments give rise to new types of cancer?’ My purpose in this paper is to discuss not only the bad, but also the good in stem cells.

Cancer is the cause of death in one out of four people in the United States.{Cronin, 2014 #124;Ward, 2014 #128} The mortality rate has been almost constant in spite of all new discoveries to cure cancer in the past few decades{Cronin, 2014 #124}. This shows that several contributing factors play major roles. The practice of clinical oncology focuses on the diversity on cancer cells.

Another reason why cancer cells are so dangerous is because they can spread to other parts of the body. Most normal cells stay where they

Tumor is a complex tissue comprising not only the malignant cells, but the surrounding stroma as well. Stroma is the microenvironment in which a tumor originates and progresses as a malignant disease. The tumor microenvironment plays critical roles in cancer pathogenesis controlling multiple events associated with the tumor development, such as tumor cell proliferation, invasion, metastasis and angiogenesis, and thus could be a focus in developing therapeutic approaches. It also can limit the access of therapeutics to the tumor, alter drug metabolism and contribute to the development of drug resistance. Because of their role in all the stages of tumor development, stromal elements represent attractive therapeutic targets. Manipulating host-tumor

The ability of cancerous cells to migrate from their primary site and invade a secondary site is a hallmark of malignant progression. The invasive potential of a tumor hinges on the rigidity of its epithelial microenvironment in vivo, or the stiffness of the matrix on which the cells are grown in vitro. The serine/threonine protein kinase Cα (PKCα) promotes cell movement and contributes to tumor invasion, partially due to its activity on two newly discovered substrates, CEP4 and α6-tubulin. We set out to characterize the role of these PKCα substrates in the invasive phenotype of an aggressive metastatic mammary carcinoma cell line LM2-4175. We hypothesized that phosphorylation-resistant mutants of CEP4 and α6-tubulin would decrease the invasive phenotype. To test this, we transiently transfected LM2-4175 cells with either wild type or phosphorylation-resistant CEP4 or α6-tubulin and studied their migratory efficiency in transwells fitted with matrices of differing stiffness. In parallel, cells were treated with a PKC activator. As predicted, migration was potentiated by stiffer matrices under all conditions, with the exception of cells transfected with phosphorylation resistant CEP4 and α6-tubulin where the invasion in the softer matrix was greater. Furthering our understanding of the individual contributions of substrates of PKCα holds clinical promise, as it will permit the development of novel targeted therapeutics to curb cell migration and metastasis.

Importantly, the ERM protein ezrin itself is a well-known mediator of metastasis (Elliott et al., 2005; Khanna et al., 2004; Meng et al., 2010). Many clinical studies have linked high expression of ezrin with poor outcome in cancer patients suffering from a wide variety of cancers, including prostate, breast can lung cancer (Clucas and Valderrama, 2014). Interestingly, specifically the abnormal distribution of ezrin in breast cancer patients, from the apical regions of non-tumorigenic cells to motile projections in invasive cells, has been correlated with poor prognosis (Sarrio et al., 2006). In addition, it has previously been indicated as an important regulator of metastasis in the murine carcinoma cell line AC2M2 (Elliott et al., 2005). Furthermore, ezrin overexpression has been shown in various studies to promote the survival, migration and/or invasion of cancer cells into surrounding tissue and to disrupt cell-cell contacts (Clucas and Valderrama, 2014).

Local invasion represents the first step of the metastatic cascade and requires profound changes in cell-cell adhesion, cell-ECM interactions, proteolysis of ECM components and acquisition of migratory properties. Cancer cells can deploy different types of cell migration, including collective migration and single cell migration50. Predominantly, most epithelial cancer cells use collective cell migration, however some cancer cells may co-opt the biological program known as the EMT to migrate as single cells. EMT is a critical process for multiple aspects of normal embryonic development51. Since its discovery, there has been the realization that there are many parallels in the mechanisms that govern EMT in embryonic development and in cancer

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