RATIONALE & HYPOTHESES
Past studies have shown that Podxl overexpression identifies a highly aggressive subset of breast carcinomas. Moreover, our previous results show an important role of Podxl on in vivo primary tumor growth and metastasis of MDA-MB-231 cells. However, the mechanism of action by which Podxl plays a role in tumor progression it still unclear. I hypothesize that the structure and biochemical and signalling properties of podocalyxin promote breast cancer tumor progression and, therefore, podocalyxin may be a novel target for future therapeutics.
OBJECTIVES & AIMS
Objective #1: Identify the Podxl functional domains required for cancer metastasis.
Aim 1.1: Generation of human Podxl mutants
Aim 1.2: Identify critical
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We have selected different hPodxl mutants to generate (Figure 5). 1) PodxlDTHL: Podxl mutant lacking the C-terminal PDZ docking site, the docking site for NHERF1/2. This mutant will allow us to determine whether or not the ability to bind NHERF1/2 is critical for tumor progression. 2) PodxlTail, lacking all but three aminoacids of the cytoplasmic tail and, therefore, eliminating all intracellular binding (ezrin, NHERF1/2 and other potential unknown ligands). 3) PodxlEC missing the whole extracellular domain, allowing us to account for the lack of the highly negatively charged glycosylated portion as well as the stalk domain.
We previously demonstrated that a high-affinity monoclonal antibody (mAb) targeting Podxl (PODOC1) could be used to block tumor growth and metastasis in a pre-clinical tumor model in mice(28). Administration of PODOC1 mAb to tumor-bearing mice inhibited primary tumor growth and attenuated distant metastases to the lung(28). The PODOC1 epitope is the stalk domain of Podxl’s extracellular portion (a core protein domain). Because other very similar anti-podocalyxin mAbs that we generated to Podxl’s extracellular core protein domains had no therapeutic effect, we post that this critical domain (the PODOC1 epitope) serves a functional role in Podxl mode of action in metastasis. Since PODOC1’s epitope appears to have a significant role in tumorigenesis, we will generate an additional hPodxl mutant (ECGlyco) lacking only the
Tlacaelel was the original emperor of the Aztec empire. He brought the empire to its height of power during the 1400s. He rewrote Aztec history by burning old documents and putting emphasis on the idea that his people were the chosen of the gods. Pre-Aztec war, the Mexicas had always been war-driven people. Their god Huitzilopochtli, the sun god, was the god of war. Although, the Aztecs actually had many different gods as the years passed.
After decades of experience, medical research is now focusing on slowing or preventing the progression of this cancer. By learning all the biochemical pathways involved in the initiation, progression, and proliferation of cancer, scientists hope that they can find ways to change how cancer develops.
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
The other influential components such as PI3K, ERK, and Ras have been previously explored in multiple cancer types. However, the influential components consist of the most important drug candidates that block cell proliferation in cancer cells. Some of these components have been associated with the drug resistance. For example, in non-small cell lung cancer, EGFR showed mutation in its kinase domain, Epithelial–mesenchymal transition, and mechanisms to develop resistance to gefitinib [35]. In colorectal, and head and neck cancers KRAS mutation, EGFR-S492R mutation, and increased ErBb signaling are responsible for resistance
CN’s dimeric structure results in high reactivity in platelet protein phosphorylation, allowing CN to bind to IIb3 and inhibiting platelet aggregation. It is also known that CN is able to bind to 1 and 3 subclasses, inhibiting many types of integrins (Lin et al. 2010). Research has shown that the two integrins that are expressed in angiogenesis and cancer metastasis are v3 and v5. Blocking v5 results in blocking the vascular endothelial growth factor, or VEGF, angiogenesis because of its involvement in cell adhesion. This integrin requires an insulin growth factor to activate to mediate cell migration. Zhou et al. (2000) has shown that CN binding to vitronectin receptors allows the inhibition of melanoma and breast cancer cells to vitronectin. In addition, v3 commonly mediates tumor cell adhesion to vitronectin. However, antagonists to this integrin can inhibit angiogenesis in endothelial cells, with CN acting as an antagonist. Many studies have tested the efficacy of CN on tumors from breast cancer, prostate cancer, and bladder cancer. For example, CN was able to inhibit the adhesion of T24 bladder carcinoma cells to vitronectin (Zhou et
CXCL9 and CXCL10 (matrix degrading enzymes) also induce tumor cells to leave the tumor and eventually form additional metastases (the development of secondary malignant growths at a distance from a primary site of cancer) at distinct sites.
Renal cell carcinoma or kidney cancer BM has been challenging to find the proper course of treatments since a large range of therapies have shown responses. There has yet to be specific biomarkers that can be identified for diagnostic purposes. Studies have shown that PI3K, AKT, and mTOR pathway are important in the development of renal carcinoma. These pathways will likely be the targets for therapy.
Such drugs are known as PKC inhibitors. This includes staurosporine, a microbial alkaloid and precursor to many novel PKC inhibitors which compete at PKC's ATP binding site. Newer drugds like N-benzoyl-staurosporin and -hydroxystauro-sporin improve selectivity and demonstrated better therapeutic effect in vivo. (21) The problem for existing PKC inhibitors is that they are relatively non-selective in their actions. In the future better drugs can be developed if they target specific isozymes in order to differentially inhibit PKC functions. (21) Some other researchers study the down stream products of PKC pathway, like vimentin, as a anti-cancer therapeutic target. For example, withaferin-A increases apoptosis and vimentin cleavage in vimentin expressing tumor cells and it has been proved that this drug has pronounced anti-antiogenic effect with little adverse effect in non-proliferating endothelial cells. (22) It also significantly blocks soft tissue sarcoma growth and
Certain proteins related to oxysterol action are already considered as potential targets for design of cancer therapeutics. For instance, activating LXR receptors could help with inhibition of proliferation. Also, targeting CYP27A1 or CYPB1 that regulate the level of 27-HC in cells may affect its role in breast carcinoma. However, the area of genetics of these markers is rather underexplored and the missing functional link to both the circulation and target tissue oxysterol levels and activity in human cancer patients precludes the translation of these results into clinical
The line that is added to the graph represents an average number which shows that podocalyxin cells (MCF-7 Podo) have a higher number of micro-nodules surrounding the primary tumor compared to the control cells (MCF-7 control). On the other hand, graph F shows the ratio of the number of tumor micro-nodules to the tumor volume. Here we can see once again that MCF-7 podocalyxin cells have a higher ratio, supporting the finding that podocalyxin overexpression regulates tumor budding by increasing its frequency.
Cancer is the second leading cause of death with 14 million new cases and 8.2 million cancer-related deaths worldwide in 2012. Despite the progress made in cancer therapies, neoplastic diseases are still a major therapeutic challenge notably because of intra- and inter-malignant tumor heterogeneity and adaptation/escape of malignant cells to/from treatment. New targeted therapies need to be developed to improve our medical arsenal and counter-act cancer progression. Human kallikrein-related peptidases (KLKs) are secreted serine peptidases which are aberrantly expressed in many cancers and have great potential in developing targeted therapies. The potential of KLKs as cancer biomarkers is well established since the demonstration of the association between KLK3/PSA (prostate specific antigen) levels and prostate cancer progression. In addition, a constantly increasing number of in vitro and in vivo studies demonstrate the functional involvement of KLKs in cancer-related processes. These peptidases are now considered key players in the regulation of cancer cell growth, migration, invasion, chemo-resistance, and importantly, in mediating interactions between cancer cells and other cell populations found in the tumor microenvironment to facilitate cancer progression. These functional roles of KLKs in a cancer context further highlight their potential in designing new anti-cancer approaches. In this review, we comprehensively review the biochemical features of KLKs, their
With a change in focus, recent advances in this field have led researchers to develop targeted anticancer agents that have the potential to reduce the side effects associated with classical chemotherapeutics, which include nephrotoxicity, neurotoxicity, leukopenia, thrombocytopenia, nausea, vomiting, and hair loss.5,6 A promising advancement in chemotherapeutics is the development of therapy that targets various biomolecules that are associated with cancer. Known as targeted therapy, this offers significant potential for increasing selectivity by synthesizing compounds that are directed towards cell signaling pathways known as important for cancer cell immortalization.7 Moreover, targeted therapy shows promise with synthesized drugs directed for cancer biomarkers because it will increase selectivity to damage cancer cells instead of healthy cells.8 The early generations of chemotherapeutics largely focused on creating more potent metal complexes, analogous to the structure and function of cisplatin.4 However, with targeted therapy as a promising advancement, the next generation of chemotherapeutics instead focuses on selectivity in the preparation of transition metal complexes that are directed toward specific biomolecules that are known to advance cancer cell
Evidence for pro-metastatic role of TAMs: Genetic studies in mice have shown decreased rates of tumor growth and metastasis are associated with decreased TAM numbers. Lin and colleagues crossed a transgenic mouse susceptible to mammary cancer with mice containing a recessive null mutation in the CSF-1 gene (Csf1op) and compared tumor progression in wild-type and mice lacking CSF1. Of note, CSF1 is an important survival factor for macrophages. They observed that the absence of CSF-1 significantly reduced lung metastases. However, transgenic expression of CSF-1 in the mammary epithelium of both Csf1op/Csf1op and wild-type tumor-prone mice led to accelerated disease progression and to a significant increase in lung metastasis, which was associated with an enhanced infiltration of TAMs into the primary tumor. In this mouse model, they also observed that TAMs play a crucial role in the ‘‘angiogenic switch” when hyperplastic lesions develop into early stage mammary carcinomas. Similarly, in another study using transplanted tumors, CSF1 depletion resulted in an impairment of tumor growth accompanied with extensive necrosis and poor vascularization, which could be reversed by treatment of mice with CSF1 (Nowicki). These studies provide strong evidence that TAMs promote malignant tumor progression.
A typical cell needs an outside mitogenic growth factor to bind to its corresponding cell surface receptor in order to become active and initiate a proliferation cascade. However, in tumor cells, oncogenes mimic these outside signaling factors and binds to receptors. The impersonating behavior result in heterotypic signaling thereupon making cancer cell hyperresponsive to induce more proliferation. For instance, HER2/neu and EGF-R/erbB are prominent receptors overexpressed in carcinomas due to continual activation of oncogenes. Furthermore, the article suggests that in 25% human tumor cells, a Ras protein is often found structurally altered. A problem with mutated Ras protein is that it
For metastatic outgrowth extravasation of tumor cells and secondary seeding are important. In secondary organs fibronectin expression is upregulated by primary tumors via resident fibroblasts, which serves as a docking site for VEGFR1+ hematopoietic progenitor cell (HPC) clusters and secondary seeding. During metastasis of breast cancer to lung, interaction of VCAM-1+ cancer cells with VLA-4-expressing macrophages, activates PI3K/Akt signaling in tumor cells, protecting them from caspase-induced apoptosis. Bone metastasis is also facilitated by interaction of VCAM1 with different integrin partner, α4β1, in osteoclasts. Thus, we can conclude that disruption of adhesion signaling between stromal cells and tumor cells can