The post-surgery limbo and the need for targeting the initial stages of the metastatic process.

Whitney Jamieson¹, Mike Russell¹, Julia D’Ambrosio¹ and Alessandro Fatatis¹^,²; ¹Department of Pharmacology and Physiology and ²Department of Pathology and Laboratory Medicine. Drexel University College of Medicine, Philadelphia, PA.

Patients affected by a wide range of solid tumors do not generally succumb to the primary neoplasia, but rather to its metastatic dissemination to secondary organs. This is particularly true for prostate and breast cancers. For instance, although 92% of women with breast cancer have a localized disease at presentation, many will eventually develop clinical metastases, sometimes years after initial treatment. The concepts that the ensuing metastatic disease is entirely determined by events that have already occurred prior to surgery and therefore not longer preventable, might not fully represent the actual clinical scenario. It is plausible that metastatic spread takes place also after breast conservative surgery and involves cancer cell departure from either residual tumor or recurrences.  The possibility that surgical excision of the primitive tumor alters the breast tissue microenvironment, thereby promoting malignant dissemination, must be investigated with appropriate animal models.

Among different metastatic sites, the colonization of the skeleton is an extremely common complication of breast and prostate cancers and many patients perish from it. The administration of bisphosphonates limits the bone-resorption observed in clinically relevant metastases; however, despite reducing osteolytic pain, these compounds are ineffective in prolonging patient survival. We have shown that the initial colonization of bone and the progression of small malignant foci may depend on tissue factors different from those responsible for the growth of macroscopic metastases. The early treatment of pre-clinical animal models with a humanized antibody against the alpha-receptor for Platelet Derived Growth Factor (alpha-PDGFR) is able to significantly counteract skeletal metastases from human prostate cancer cells. As this receptor can confer bone-tropism to cancer cells, we are conducting comparative transcriptomic analyses to identify specific gene-expression profiles promoted by alpha-PDGFR and that may be responsible for the initial colonization of the skeleton by prostate cancer cells.

The development of adjuvant therapies against infiltration and early colonization of distant organs by cancer cells immediately after initial surgery will lead to a change in the treatment of a large subset of patients and may significantly contribute to reducing lethal metastatic complications.

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