Mechanisms affecting the homing, engraftment and functioning of hematopoietic stem cells in a compromised bone marrow environment: relevance to treatment of the elderly cancer patient by stem cell therapy

Most people diagnosed with cancer, including a variety of life-threatening hematologic malignancies, are over 65 years old. The options and outcomes of treating the elderly cancer patient with hematopoietic stem cell (HSC) therapy are limited. Achieving better long-term engraftment following transplantation in this growing target group will rely on profound knowledge of the interactions between HSCs and the bone marrow (BM) environment, specifically in the compromised settings of the aged. Recently, we generated mice deficient in the cell-cell adhesion signaling components p120ctn and a-E-catenin in skeletal progenitors. Our preliminary data indicate that the mice display low bone mass, increased marrow adiposity, and alterations in the BM vasculature. Since these components represent established niches regulating HSC homing, quiescence and differentiation, we hypothesize that hematopoietic functioning may be affected. Interestingly, the phenotype resembles typical skeletal complications of ageing, osteoporosis, and cancer treatments such as irradiation and chemotherapy. Thus, these mice present pertinent models to study the interplay between these compromised niches and endogenous as well as transplanted HSCs, and the involvement of p120ctn or a-E-catenin signaling in osteo-lineage cells. This information could be used in the future to develop engraftment-enhancing treatment strategies, such as appropriate niche-modulating drugs, to improve cancer control in older patients.