A new Neu-a syngeneic model of spontaneously metastatic HER2-positive breast cancer.

Metastatic disease results from the dissemination of tumor cells beyond their organ of origin to grow in distant organs and is the primary cause of death in patients with advanced breast cancer. Preclinical murine models in which primary tumors spontaneously metastasize are valuable tools for studying metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. The NT2.5-lung metastasis (-LM) cell line was derived from serial passaging of tumor cells that were macro-dissected from spontaneous lung metastases after orthotopic mammary implantation of parental NT2.5 cells. Within one week of NT2.5-LM implantation, metastases are observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. We demonstrate that NT2.5-LM metastases are positive for NeuN-the murine equivalent of human epidermal growth factor 2 (HER2). We further demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT), suggestive of their enhanced metastatic potential. Genomic analyses support these findings and reveal enrichment in EMT-regulating pathways. In addition, the metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. The new NT2.5-LM model provides certain advantages over the parental NT2/NT2.5 model, given its more rapid and spontaneous development of metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses.

Mimicking the breast metastatic microenvironment: characterization of a novel syngeneic model of HER2+ breast cancer.

Preclinical murine models in which primary tumors spontaneously metastasize to distant organs are valuable tools to study metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line, NT2.5-lung metastasis (-LM), that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. Within one week of orthotopic implantation of NT2.5-LM in NeuN mice, distant metastases can be observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. Metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. We demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT) and enrichment in EMT-regulating pathways, suggestive of their enhanced metastatic potential. The new NT2.5-LM model provides more rapid and spontaneous development of widespread metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses targeting distant visceral metastases.

An emerging paradigm of CXCL12 involvement in the metastatic cascade.

The chemokine CXCL12, also known as stromal cell-derived factor 1 (SDF1), has emerged as a pivotal regulator in the intricate molecular networks driving cancer progression. As an influential factor in the tumor microenvironment, CXCL12 plays a multifaceted role that spans beyond its traditional role as a chemokine inducing invasion and metastasis. Indeed, CXCL12 has been assigned functions related to epithelial-to-mesenchymal transition, cancer cell stemness, angiogenesis, and immunosuppression, all of which are currently viewed as specialized biological programs contributing to the "metastatic cascade" among other cancer hallmarks. Its interaction with its cognate receptor, CXCR4, initiates a cascade of events that not only shapes the metastatic potential of tumor cells but also defines the niches within the secondary organs that support metastatic colonization. Given the profound implications of CXCL12 in the metastatic cascade, understanding its mechanistic underpinnings is of paramount importance for the targeted elimination of rate-limiting steps in the metastatic process. This review aims to provide a comprehensive overview of the current knowledge surrounding the role of CXCL12 in cancer metastasis, especially its molecular interactions rationalizing its potential as a therapeutic target.

A Proposed Link Between Acute Thymic Involution and Late Adverse Effects of Chemotherapy.

Epidemiologic data suggest that cancer survivors tend to develop a protuberant number of adverse late effects, including second primary malignancies (SPM), as a result of cytotoxic chemotherapy. Besides the genotoxic potential of these drugs that directly inflict mutational burden on genomic DNA, the precise mechanisms contributing to SPM development are poorly understood. Cancer is nowadays perceived as a complex process that goes beyond the concept of genetic disease and includes tumor cell interactions with complex stromal and immune cell microenvironments. The cancer immunoediting theory offers an explanation for the development of nascent neoplastic cells. Briefly, the theory suggests that newly emerging tumor cells are mostly eliminated by an effective tissue immunosurveillance, but certain tumor variants may occasionally escape innate and adaptive mechanisms of immunological destruction, entering an equilibrium phase, where immunologic tumor cell death "equals" new tumor cell birth. Subsequent microenvironmental pressures and accumulation of helpful mutations in certain variants may lead to escape from the equilibrium phase, and eventually cause an overt neoplasm. Cancer immunoediting functions as a dedicated sentinel under the auspice of a highly competent immune system. This perspective offers the fresh insight that chemotherapy-induced thymic involution, which is characterized by the extensive obliteration of the sensitive thymic epithelial cell (TEC) compartment, can cause long-term defects in thymopoiesis and in establishment of diverse T cell receptor repertoires and peripheral T cell pools of cancer survivors. Such delayed recovery of T cell adaptive immunity may result in prolonged hijacking of the cancer immunoediting mechanisms, and lead to development of persistent and mortal infections, inflammatory disorders, organ-specific autoimmunity lesions, and SPMs. Acknowledging that chemotherapy-induced thymic involution is a potential risk factor for the emergence of SPM demarcates new avenues for the rationalized development of pharmacologic interventions to promote thymic regeneration in patients receiving cytoreductive chemotherapies.