The interplay between a tumor and its environment is exemplified by the morphological changes observed in the stroma of human breast cancer. These changes are evident as stromal myxoid changes. Hyaluronan, an extracellular polysaccharide that has been implicated in invasion, is one of the major constituents of the stromal myxoid changes. This study evaluated the association of these stromal changes with axillary node status, tumor grade, and mortality. The prognostic value of the stromal myxoid changes was evaluated in patients with negative axillary nodes with 10 years of follow-up. Our results showed a high level of reproducibility of our stromal myxoid changes grading system (overall kappa ‫؍‬ 0.68). Image analysis semiquantification showed marked correlation of a strong stromal hyaluronan signal with high-grade stromal myxoid changes. In a multiple logistic regression analysis, positive nodes were associated with stromal myxoid changes, tumor size, desmoplasia, lymphocytic infiltration, high tumor grade, tumor emboli, and multifocality. Stromal myxoid changes were also associated with young age and lymphatic embolizations (P < .001). Overall, there is a weak correlation between mortality and stromal myxoid changes (P < .01). Mortality was more evident with high stromal myxoid changes grades and tumor size >2 cm (P < .008). However Cox multivariate analysis fail to show stromal myxoid changes as an independent prognostic factor. In conclusion, stromal myxoid changes with high hyaluronan concentration are strongly associated with positive nodes, tumor grade, and lymphatic emboli, thereby identifying high-risk group and reinforcing the role of hyaluronan in invasion and metastasis.KEY WORDS: Breast cancer, Hyaluronan, Metastasis, Stroma. Mod Pathol 2003;16(2):99 -107Lymph node and hematogenous distant metastases are the result of a cascade of enzymatic interactions. Part of this complex cascade takes place in the tumor environment, where malignant tumor cells detach from the primary tumor, adhere to components of the extracellular matrix, degrade them, and move through the stroma. Morphological and biochemical modifications of the different stromal components (cellular and noncellular) can either favor or inhibit this process. Therefore, the histopathological modifications of the stroma in response to a tumor could shed light on the biological mechanisms involved in invasion and metastasis. Stromal myxoid changes consists of a stromal reaction composed of an amphophilic or slightly basophilic vacuolated material that stains positively with Alcian Blue and is found among the collagen fibers. Hyaluronan is one of its major components. Tissues rich in hyaluronan entrap water and swell, leading to myxoid changes. It is known that hyaluronan synthesis is stimulated by the interaction between tumor and stromal cells (1-3). Hyaluronan has several physiological functions, such as water homeostasis and regulation of capillary growth; it also plays a role in cell recognition and migration (4). A strong relationship betwe...

Tumour cells can find in bone marrow (BM) a niche rich in growth factors and cytokines that promote their self-renewal, proliferation and survival. In turn, tumour cells affect the homeostasis of the BM and bone, as well as the balance among haematopoiesis, osteogenesis, osteoclastogenesis and bone-resorption. As a result, growth and survival factors normally sequestered in the bone matrix are released, favouring tumour development. Mesenchymal stem cells (MSCs) from BM can become tumour-associated fibroblasts, have immunosuppressive function, and facilitate metastasis by epithelial-to-mesenchymal transition. Moreover, MSCs generate osteoblasts and osteocytes and regulate osteoclastogenesis. Therefore, MSCs can play an important pro-tumorigenic role in the formation of a microenvironment that promotes BM and bone metastasis. In this study we showed that BM MSCs from untreated advanced breast and lung cancer patients, without bone metastasis, had low osteogenic and adipogenic differentiation capacity compared to that of healthy volunteers. In contrast, chondrogenic differentiation was increased. Moreover, MSCs from patients had lower expression of CD146. Finally, our data showed higher levels of Dkk-1 in peripheral blood plasma from patients compared with healthy volunteers. Because no patient had any bone disorder by the time of the study we propose that the primary tumour altered the plasticity of MSCs. As over 70 % of advanced breast cancer patients and 30-40 % of lung cancer patients will develop osteolytic bone metastasis for which there is no total cure, our findings could possibly be used as predictive tools indicating the first signs of future bone disease. In addition, as the MSCs present in the BM of these patients may not be able to regenerate bone after the tumour cells invasion into BM/bone, it is possible that they promote the cycle between tumour cell growth and bone destruction.