Intravital microscopy of osteolytic progression and therapy response of cancer lesions in the bone

Dear editor,

We read with great interest the recent publication by Eleonora Dondossola and colleagues [1] who development very ingenious new methods for the study of osteolytic progression and therapy response of cancer lesions in the bone. To this end, authors combined a tissues-engineered mature micro-ossicle with skin windows-based intravital multiphoton microcopy (iMPM) to provide a new strategy for longitudinal analysis of tumor cells interaction with bone environment, as well as for the study of cancer associated-osteolysis and/or therapy response.

In our opinion, the approaches proposed in this study [1] can drastically change the current knowledge about the biology of bone metastasis, mainly from epithelial cancers, opening interesting prospective for the development of specific new anti-metastatic drugs capable to prevent or block this pathological process. In fact, despite the numerous investigations about the molecular mechanisms involved in the formation of osteolytic bone lesions, efficient therapies have not yet been developed. The therapeutic strategies currently available are able to induce bone pain palliation rather than enhanced survival [2]. Thus, the management of patients affected by bone metastatic lesions represent one of the most important healthcare issue in worldwide. As mentioned by Dondossola et al. [1], the more frequent epithelial lesions that develop bone metastasis are breast and prostate cancers.

Breast cancer tumors display an extraordinary inclination to grow in bone [3]. About 10 % of all breast cancer patients without evidence of bone metastases at the time of diagnosis will have a first relapse in bone within five years of their primary diagnosis [4]. Furthermore, 65–75% of patients with advanced breast cancer will develop bone metastases [4]. Bone involvement in breast cancer can heavily affect quality of life because of pathologic bone fractures, bone pain, hypercalcemia and spinal cord compression. Additionally, these complications contribute significantly to the cost of care [5]. In contrast to breast cancer, prostate metastasis to the bone often results in osteoblastic lesions, though it is known that prostate cancer lesions display both blastic and lytic characteristics during the early phases of the metastatic process [6]. Even though the mechanisms of osteoblastic and osteolytic responses in prostate cancer are not fully understood, it is clear that many factors involved in osteolytic breast cancer bone metastasis also regulate the osteolytic aspects of prostate cancer. In this scenario, we recently described, both in breast and in prostate primary lesions, a new cancer cell type showing morphological, ultrastructural and molecular characteristics of osteoblasts [7,8]. On note, we demonstrated a putative correlation between the presences of breast osteoblast-like cells (BOLCs) in primary cancers and the formation of osteolytic bone metastasis within the five years of from the first diagnosis [9]. From molecular point of view, we have proposed a mechanisms for the BOLCs origin. Specifically, our data allowed us to hypothesise that breast epithelial cells that acquire mesenchymal characteristics by the epithelial to mesenchymal transition (EMT) phenomenon can assume an osteoblast-like phenotype under the induction of bone inducing factors expressed in breast environment such as “Bone Morphogenetic Proteins” (BMPs) [7] and PTX3 [10]. Starting from these ex vivo data, we are also developing a colure methods for the “production” of BOLCs.
In this regards, the technology described by Dondossola and colleagues could provide the unequivocal proof of the direct involvement of BOLCs in the formation of breast cancer metastasis to bone. In fact, through the use of iMPM would become the identification of a) the characteristic molecular “imprint” of BOLCs, b) the interaction between BOLCs and bone environment (especially osteoclasts) and c) the possible molecular adaptation of BOLCs during all phases of bone metastasis formation. Thus, the characterization of genetic/molecular events related to both BOLCs formation and activity by iMPM can lay the foundation for the development of innovative diagnostic tools for the early detection of cancers lesions with high-propensity to form bone metastasis. Even more important, the applications here proposed open the way for the identification of new targets for therapies directed against BOLCs that could significantly improve the management of patients and ameliorate their prognosis and quality of life.

Finally, we think that the iMPM technology is particularly suitable for the study of the biological and molecular characteristic of main age-related bone disorders in which the alteration of the physiological interaction between osteoblasts and osteoclasts is often the main cause of disease progression.

Competing interests: The authors declare that they have no competing interests.

Reference
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