A Novel Metastatic Estrogen Receptor-Expressing Breast Cancer Model with Antiestrogen Responsiveness.

Most women diagnosed with breast cancer (BC) have estrogen receptor alpha-positive (ER+) disease. The current mouse models of ER+ BC often rely on exogenous estrogen to encourage metastasis, which modifies the immune system and the function of some tissues like bone. Other studies use genetically modified or immunocompromised mouse strains, which do not accurately replicate the clinical disease. To create a model of antiestrogen responsive BC with spontaneous metastasis, we developed a mouse model of 4T1.2 triple-negative (TN) breast cancer with virally transduced ER expression that metastasizes spontaneously without exogenous estrogen stimulation and is responsive to antiestrogen drugs. Our mouse model exhibited upregulated ER-responsive genes and multi-organ metastasis without exogenous estrogen administration. Additionally, we developed a second TN BC cell line, E0771/bone, to express ER, and while it expressed ER-responsive genes, it lacked spontaneous metastasis to clinically important tissues. Following antiestrogen treatment (tamoxifen, ICI 182,780, or vehicle control), 4T1.2- and E0771/bone-derived tumor volumes and weights were significantly decreased, exemplifying antiestrogen responsivity in both cell lines. This 4T1.2 tumor model, which expresses the estrogen receptor, metastasizes spontaneously, and responds to antiestrogen treatment, will allow for further investigation into the biology and potential treatment of metastasis.

Bone Marrow-Derived Stem Cell Factor Regulates Prostate Cancer-Induced Shifts in Pre-Metastatic Niche Composition.

Skeletal metastasis is the leading cause of morbidity and mortality in prostate cancer, with 80% of advanced prostate cancer patients developing bone metastases. Before metastasis, bone remodeling occurs, stimulating pre-metastatic niche formation and bone turnover, and platelets govern this process. Stem cell factor (SCF, Kit Ligand) is increased in advanced prostate cancer patient platelet releasates. Further, SCF and its receptor, CD117/c-kit, correlate with metastatic prostate cancer severity. We hypothesized that bone-derived SCF plays an important role in prostate cancer tumor communication with the bone inducing pre-metastatic niche formation. We generated two cell-specific SCF knockout mouse models deleting SCF in either mature osteoblasts or megakaryocytes and platelets. Using two syngeneic androgen-insensitive murine prostate cancer cell lines, RM1 (Ras and Myc co-activation) and mPC3 (Pten and Trp53 deletion), we examined the role of bone marrow-derived SCF in primary tumor growth and bone microenvironment alterations. Platelet-derived SCF was required for mPC3, but not RM1, tumor growth, while osteoblast-derived SCF played no role in tumor size in either cell line. While exogenous SCF induced proangiogenic protein secretion by RM1 and mPC3 prostate cancer cells, no significant changes in tumor angiogenesis were measured by immunohistochemistry. Like our previous studies, tumor-induced bone formation occurred in mice bearing RM1 or mPC3 neoplasms, demonstrated by bone histomorphometry. RM1 tumor-bearing osteoblast SCF knockout mice did not display tumor-induced bone formation. Bone stromal cell composition analysis by flow cytometry showed significant shifts in hematopoietic stem cell (HSC), mesenchymal stem cell (MSC), and osteoblast cell percentages in mice bearing RM1 or mPC3 tumors. There were no significant changes in the percentage of macrophages, osteoclasts, or osteocytes. Our study demonstrates that megakaryocyte/platelet-derived SCF regulates primary mPC3 tumor growth, while SCF originating from osteoblasts plays a role in bone marrow-derived progenitor cell composition and pre-metastatic niche formation. Further, we show that both the source of SCF and the genetic profile of prostate cancer determine the effects of SCF. Thus, targeting the SCF/CD117 signaling axis with tyrosine kinase inhibitors could affect primary prostate carcinomas or play a role in reducing bone metastasis dependent on the gene deletions or mutations driving the patients' prostate cancer.

Tissue distribution of stem cell factor in adults.

Stem cell factor (SCF) is an essential cytokine during development and is necessary for gametogenesis, hematopoiesis, mast cell development, stem cell function, and melanogenesis. Here, we measure SCF concentration and distribution in adult humans and mice using gene expression analysis, tissue staining, and organ protein lysates. We demonstrate continued SCF expression in many cell types and tissues into adulthood. Tissues with high expression in adult humans included stomach, spleen, kidney, lung, and pancreas. In mice, we found high SCF expression in the esophagus, ovary, uterus, kidney, and small intestine. Future studies may correlate our findings of increased, organ-specific SCF concentrations within adult tissues with increased risk of SCF/CD117-related disease.

Comparative Approach to the Temporo-Spatial Organization of the Tumor Microenvironment.

The complex ecosystem in which tumor cells reside and interact, termed the tumor microenvironment (TME), encompasses all cells and components associated with a neoplasm that are not transformed cells. Interactions between tumor cells and the TME are complex and fluid, with each facet coercing the other, largely, into promoting tumor progression. While the TME in humans is relatively well-described, a compilation and comparison of the TME in our canine counterparts has not yet been described. As is the case in humans, dog tumors exhibit greater heterogeneity than what is appreciated in laboratory animal models, although the current level of knowledge on similarities and differences in the TME between dogs and humans, and the practical implications of that information, require further investigation. This review summarizes some of the complexities of the human and mouse TME and interjects with what is known in the dog, relaying the information in the context of the temporo-spatial organization of the TME. To the authors' knowledge, the development of the TME over space and time has not been widely discussed, and a comprehensive review of the canine TME has not been done. The specific topics covered in this review include cellular invasion and interactions within the TME, metabolic derangements in the TME and vascular invasion, and the involvement of the TME in tumor spread and metastasis.