STOPCa · The cryptic path of tumor-microenvironment interactions in prostate cancer

The cryptic path of tumor-microenvironment interactions in prostate cancer

Prostate cancer (PCa) is the most frequent cancer in men and the second leading cause of cancer-associated death in men. Metastasis to other organs is the main cause of cancer-related mortality. PCa frequently metastasizes to the bone, with no curative treatments being currently available. Widespread screening of prostate specific antigen (PSA) is often associated with overdiagnosis and overtreatment of low-risk PCa, associated with high socioeconomic impact, while there is a lack of diagnostic tools to identify patients in high risk of metastasis. Understanding the mechanisms of tumor progression to metastatic stage is necessary for the design of therapeutic and prognostic schemes. An important component of tumor growth is the supportive stroma/microenvironment: the extracellular matrix (ECM) and the non-tumoral stroma cells. However, it is unclear whether the stroma is modulated by the tumor cells or by intrinsic abnormal alterations. The preferential metastasis to the bone, also suggests that optimal conditions for the PCa cell growth exist in that microenvironment and may facilitate this process. The bi-directional influence of tumor and stroma, along with tumor heterogeneity multiplies the degree of complexity, thus in STOPCa we sought to elucidate the tumor-stroma interactions which is critical for the proper design of diagnostic tools/ putative therapies. Action objectives We hypothesized that bone metastatic, stroma-specific molecular signature may be conserved in tumor models even in diffenent (non bone) microenvironments. The main objective of the STOPCa was to determine whether the stroma of metastatic PCa contains a specific (pre)metastatic gene expression signature which may be detectable in primary PCa either prior to or during metastasis and act as prognosis factor. Aim 1. To identify the molecular transcriptome of tumor and tumor-stroma cells in patient-derived xenograft models Aim 2. To uncover the mechanisms of tumor-stroma interactions and their prognostic value Conclusions Our data show that metastatic PCa PDXs, that differ in androgen sensitivity, trigger a differential stroma response suggesting that stroma is influenced by tumor cues. Selected stromal markers commonly found in bone metastatic sites were induced in the microenvironment of the host organism in metastatic xenografts, although implanted in a non-bone site, indicating a “transcriptional memory” mechanism inherited by tumor cells and inducing a stromal premetastatic signature with high potential prognostic/ diagnostic value. 1. Conservation of bone metastasis stromal signature genes in other PDXs from BM, maintained in non-bone microenvironment. 2. Proof of modulation of stromal cells by tumor cells, which is specific to the tumor properties. 3. Molecular identification of transcriptome of androgen-dependent and androgen independent stroma. 4. Identification of key stromal proteins involved in the crosstalk with tumor cells with prognostic value assessed in clinical PCa cases

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз