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The role of Connective Tissue Growth Factor in breast cancer metastasis
Metastasis, dissemination of cancer cells from the site of origin to distant odrgans, is the most common cause of cancer related death. An unusual feature of metastatic cancer cell is tissue tropism, namely preference to grow in certain organs. In the case of breast cancer, the cancer cells generally metastasize from breast to bone and cause osteolytic (bone dissolving) lesions. Little is known about the molecular mechanisms underlying this process. Through gene expression profiling, a recent study identified a group of genes whose up-regulated expressions in cancer cells enhance breast-to-bone cancer metastasis. One gene among them encodes a multi-modular secreted protein, Connective Tissue Growth Factor (CTGF). To date nothing is known about how CTGF promotes metastasis. Therefore, it will be very beneficial for clinical therapies development if we can understand the molecular and cellular mechanisms behind CTGF’s effects. Here I propose following research aims to investigate the CTGF’s roles in metastasis. First, by over-expression of individual domains of CTGF or related proteins in human cancer cells followed by xenograft mouse model, I will determine specific domains of CTGF that enhance metastasis. Second, I will study the effects of CTGF in bone metastasis through pathology analysis of a xenograft model. I will compare the bone lesions caused by human breast cancer cells with or without over-expressed CTGF and define specific cell types targeted by CTGF. Third, based on the results of the second aim, I will develop in vitro cell culture assays to study CTGF’s downstream signaling pathways. I will use either gene expression profiling or chemical genetics type methods to solve the problems. Finally, I will study the clinical relevance of CTGF by examining CTGF’s expression level in tissues samples from patients with cancer metastasis. The proposed studies will greatly enrich our understanding of CTGF’s roles in cancer metastasis and therefore reveal potential targets for breast cancer treatments.
Metastasis is a treacherous process that causes the most cancer related death. In this process, cancer cells escape its original site like “seeds”, travel in human body and eventually grow in another health organ. Different types of cancers usually like to metastasize to specific organs. In the case of breast cancer, the cancer cells like to colonize and dissolve bone structures. A recent study found that excessive amount of protein factors of certain genes in breast cancer cells will promote cancer’ metastasis ability. One of such protein factors is Connective Tissue Growth Factor (CTGF), which is comprised of several protein domains. To date nothing is known about how CTGF promotes metastasis. If we can understand the working mechanisms of CTGF in metastasis, we will be able to develop drugs to control breast cancer metastasis and save a lot of lives. Here I propose following research aims to investigate the CTGF’s roles in metastasis. First, I will investigate which domains of CTGF are essential to metastasis enhancement. I will generate human breast cancer cells that produce high levels of each domain of CTGF. I will then transplant the cells to mice and assess which domain causes most metastasis. Second, I will study the effects of CTGF in bone metastasis through pathology (study of structure and functional nature of disease) analysis of mice transplanted with human breast cancer cells. I will assess the impact of CTGF on bone lesions and define specific cell types targeted by CTGF. Third, based on the results of the second aim, I will develop assays to study signaling pathways that are activated inside the cells by CTGF. I will use either DNA-chip technology or chemicals inhibiting various cell signaling molecules to determine what signaling pathways are turned on by CTGF. Finally, I will seek to determine whether CTGF is commonly seen in many patients with breast cancer metastasis. I will examine whether there is a remarkable amount of CTGF in tissues samples from various patients. The proposed studies will greatly enrich our understanding of CTGF’s roles in cancer metastasis and therefore reveal potential targets for breast cancer treatments.