Mortality and morbidity in patients with solid tumors invariably results from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited. In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell-cell adhesion, cell-matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities.
Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. Here we show that Ubc13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by BCa cells. Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.ubiquitination-mediated signaling | pre-clinical studies B reast cancer (BCa) is the leading invasive cancer among women worldwide. BCa-related mortality is usually caused by distant metastases rather than primary tumors (1, 2). The spread of cancer cells from primary tumors to distant organs, termed metastasis, is a multistep process in which cancer cells must (i) invade through the extracellular matrix (ECM), (ii) disseminate into the bloodstream, (iii) survive in the circulation, and (iv) extravasate and successfully colonize distant sites (3). Conventional therapeutic strategies have limited success in preventing and treating metastatic cancer, and BCa metastases can recur many years after removal of the primary tumor. This phenomenon could be due to the complex nature of metastasis itself, and, more realistically, the limitation of current treatments that are effective against primary BCa, i.e., surgical removal and localized radiotherapy, but do little to prevent metastatic recurrence. Even chemotherapy is not very effective against metastatic tumors (4). Unfortunately, the pharmaceutical industry has been reluctant to conduct metastasis prevention trials on patients with early stage cancer using survival and reduction of metastatic load as end points, because such studies are lengthy and require a large number of patients with otherwise relatively good survival prospects (4). Consequently, the development of agents that prevent metastasis from occurring and trigger regression of established metastatic lesions is an urgent unmet need.It was reported that expression of the ubiquitin conjugating enzyme (E2) Ubc13 is up-regulated in metastatic BCa (5). Ubc13, which heterodimerizes with Uev1a, catalyzes formation of lysine 63 (K63)-linked polyubiquitin chains, which control protein-protein interactions involved in DNA damage repair and protein kinase activation (6, 7). In certain immune cells, Ubc13 is required for IκB kinase (IKK)-nuclear factor κB (NF-κB) activation, but a more ubiquitous role for Ubc13 was observed in the activation of MAPK signaling (8-11). We found that Ubc13 is required for activation of mitogen-a...
The dissemination of prostate cancer to bone is a common, incurable aspect of advanced disease. Prevention and treatment of this terminal phase of prostate cancer requires improved molecular understanding of the process as well as markers indicative of molecular progression. Through biochemical analyses and loss-of-function in vivo studies we demonstrate that the cell adhesion molecule ALCAM is actively shed from metastatic prostate cancer cells by the sheddase ADAM17 in response to TGFβ. Not only is this post-translational modification of ALCAM a marker of prostate cancer progression, the molecule is also required for effective metastasis to bone. Biochemical analysis of prostate cancer cell lines reveal that ALCAM expression and shedding is elevated in response to TGFβ signaling. Both in vitro and in vivo shedding is mediated by ADAM17. Longitudinal analysis of circulating ALCAM in tumor-bearing mice revealed that shedding of tumor, but not host-derived ALCAM is elevated during growth of the cancer. Gene-specific knockdown of ALCAM in bone-metastatic PC3 cells greatly diminished both skeletal dissemination and tumor growth in bone. The reduced growth of ALCAM knockdown cells corresponded to an increase in apoptosis (Caspase-3) and decreased proliferation (Ki-67). Together these data demonstrate that the ALCAM is both a functional regulator as well as marker of prostate cancer progression.
During metastasis cancer cells disseminate from the primary tumor, invade into surrounding tissues, and spread to distant organs. Metastasis is a complex process that can involve many tissue types, span variable time periods, and often occur deep within organs, making it difficult to investigate and quantify. In addition, the efficacy of the metastatic process is influenced by multiple steps in the metastatic cascade making it difficult to evaluate the contribution of a single aspect of tumor cell behavior. As a consequence, metastasis assays are frequently performed in experimental animals to provide a necessarily realistic context in which to study metastasis. Unfortunately, these models are further complicated by their complex physiology. The chick embryo is a unique in vivo model that overcomes many limitations to studying metastasis, due to the accessibility of the chorioallantoic membrane (CAM), a well-vascularized extra-embryonic tissue located underneath the eggshell that is receptive to the xenografting of tumor cells (figure 1). Moreover, since the chick embryo is naturally immunodeficient, the CAM readily supports the engraftment of both normal and tumor tissues. Most importantly, the avian CAM successfully supports most cancer cell characteristics including growth, invasion, angiogenesis, and remodeling of the microenvironment. This makes the model exceptionally useful for the investigation of the pathways that lead to cancer metastasis and to predict the response of metastatic cancer to new potential therapeutics. The detection of disseminated cells by species-specific Alu PCR makes it possible to quantitatively assess metastasis in organs that are colonized by as few as 25 Freshly laid fertilized chicken eggs are incubated in a rotating incubator for 10 days at 100°F and 60% humidity. The eggs are rotated four times each hour. 2. On developmental day 10 the eggs are placed on their side in an egg rack. A goose-neck lamp or other suitable light source is used to candle the eggs by shining the light into the eggshell at the blunt end of the egg where the airsac is located. 3. The chorioallantoic vein is located and marked. This vein is located at the top of the eggshell where it is the junction of several large blood vessels. At this branch point the blood vessel drops down, away from the CAM and attaches to the embryo. A 1cm square box is drawn with pencil on the eggshell approximately 1cm away from the branch point in the vein. The area including and around the square is then cleaned using a cotton swab soaked in iodine. 4. Using a rotating cutting tool (Dremel) fitted with a silicone carbide grinding stone (Dremel part #84922) a hole is drilled through the blunt end of the egg into the air sac. Using this same tool a hole is drilled within the previously drawn square on top of the egg, stopping short of the eggshell membrane. A 25-gauge syringe needle with a fine bur on the end is used to make a small hole in the eggshell membrane being careful not to tear the underlying CAM. The CAM is s...
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