Molecular Evidence-Based Use of Bone Resorption-Targeted Therapy in Prostate Cancer Patients at High Risk for Bone Involvement

Dimitrios Karamanolakis,Athanassios Tsintavis,Despina Tiblalexi,Antigone Sourla,Constantine Milathianakis,Roxane Tenta,Peter Lembessis,Michael Koutsilieris,John Bogdanos

doi:10.1007/bf03402030

Dimitrios Karamanolakis, Athanassios Tsintavis + Show 7 more

Open Access

https://doi.org/10.1007/bf03402030

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Abstract

To improve median survival of patients with prostate cancer that has metastasized to bone, we need to better understand the early events of the metastatic process in skeleton and develop molecular tools capable of detecting the early tumor cell dissemination into bones (micrometastasis stage). However, the initial phase of tumor cell dissemination into the bone marrow is promptly followed by the migration of tumor cells into bone matrix, which is a crucial step that signals the transformation of micrometastasis to macrometastasis stage and clinically evident metastasis. The migration of cancer cells into bone matrix requires the activation of local bone resorption. Such an event contributes to tumor cell hiding/ escaping from high immunologic surveillance of bone marrow cells. Within bone matrix, tumor cells are establishing plethoric cell-cell interactions with bone marrow-residing cells, ensuring their survival and growth. Recently, RT-PCR detections of tumor marker transcripts, such as PSA and PSMA mRNA performed in RNA extracts of peripheral blood nucleated cells and bone marrow biopsy, have enabled the stratification of patients with clinically localized prostate cancer being of high risk for extraprostatic disease and bone involvement. Therefore, it is conceivable that bisphosphonate blockade of bone resorption can inhibit the migration of tumor cells into bone matrix during the early phase of disease dissemination into bone marrow (micrometastasis stage). Consequently, assessment of the efficacy and efficiency of bisphosphonates to arrest the evolution of bone lesions in this particular clinical setting of patients with clinically localized prostate cancer and positive molecular staging status (high risk for bone involvement) is warranted.

Highlights

The most important clinical manifestation of cancer, which defines treatment strategy, disease prognosis and overall survival, is tumor cell dissemination into organs distant from the primary tumor [1]
The process of metastasis implicates a cascade of events, involving angiogenesis, detachment from the primary tumor, migration into the adjacent tissue, adhesion onto the wall and entry into the local vessels, dissemination through the systemic circulation, survival in peripheral blood, extravasations, attachment onto specific organs, and local ectopic/metastatic growth in host tissue [1,2,3]
Treatment with zoledronic acid resulted in a significant (25%) reduction in the proportion of patients with a skeletal-related event (SRE) and significantly reduced the skeletal morbidity rate (SMR) for all SREs compared with placebo

Summary

Introduction

The most important clinical manifestation of cancer, which defines treatment strategy, disease prognosis and overall survival, is tumor cell dissemination (metastasis) into organs distant from the primary tumor [1]. The unusual presentation of hypercalcemia and its favorable response to bisphosphonate therapy suggest, under certain circumstances, that the resorptive component of the skeletal disease may become predominant even in prostate cancer with osteoblastic metastasis The latter can be either radiologically detected and/or histologically proven by the presence of an increased number of osteoclasts in metastatic sites [35,36,37]. The migration of tumor cells into bone matrix signals the transformation of micrometastasis stage, a diffuse dissemination of tumor cells into bone marrow to macrometastasis stage, which is mainly characterized by focal development of bony lesions [2,3,4,5,6,68] This mechanism, which enables the migration of tumor cells into bone marrow, involves the activation of osteoclast-mediated bone resorption locally. Thereafter, late events taking place between tumor cells, already located into bone matrix and bone matrix-residing cells (osteoblast-osteocytes) will favor either the predominance of bone formation or the bone destruction, thereby resulting in the final histologic type of bony lesions (blastic, lytic or mixed) (Fig. 4)

TUMOR CELL INVASION INTO BONE MATRIX

Findings

Conclusion