#Agilent 34972a the signal path Activator

More than 50% of tumor samples from breast cancer patients show evidence of activated JAK signaling 8. Activated JAKs phosphorylate the STAT proteins, which in turn dimerize and translocate to the nucleus to activate several pathways involved in tumor cell survival, proliferation, and immune evasion 7. The JAK proteins are associated with tyrosine kinase receptors activated by cytokines and growth factors 6. Due to extensive studies linking JAK/STAT signaling to oncogenic functions in cancer cells, JAK inhibitors are being investigated in the clinic for treatment of solid tumors and hematological malignancies 6.

#Agilent 34972a the signal path Activator

The Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is an oncogenic transcription factor pathway activated in tumor cells 6. By virtue of their proximity to the tumor, inhibitors are likely to affect their target pathways in TAMs as well. In order to understand how macrophages contribute to therapeutic responsiveness in tumors, is it important to define how these inhibitors impact macrophage function. Several approaches for targeting macrophage recruitment, survival, and activation in the TME have been successful in pre-clinical models of cancer and have also led to investigations in clinical trials 5.

Macrophages also mediate resistance of tumor cells to tumor-directed inhibitors, by activating compensatory survival pathways 5. TAMs regulate the growth and progression of the tumor either by directly influencing the tumor cells or by manipulating the TME by promoting angiogenesis, modifying the components of the extracellular matrix, promoting stem-ness, and by inhibiting immune response against the tumor 4.

While the effects of macrophages on tumor cell behavior are complex and often context dependent, they are thought to correlate with poor prognosis in breast cancer 2, 3. Tumor associated macrophages (TAMs) are important components of the tumor microenvironment (TME) that greatly influence tumor growth and progression 1. Thus, the impact of the tumor microenvironment is an important consideration in studying breast cancer and understanding such mechanisms of resistance is critical to development of effective targeted therapies. Furthermore, inhibition of the NF-κB pathway improves the ability of ruxolitinib to reduce mammary tumor growth in vivo. This study demonstrates that exposure of macrophages to JAK inhibitors leads to activation of NF-κB signaling, which results in increased expression of genes known to be associated with therapeutic resistance. One such pathway is the janus kinase (JAK)/signal transducer and activator or transcription (STAT) pathway, which is activated in both breast cancer cells and in tumor associated macrophages. Effective targeting of oncogenic signaling pathways in tumors requires an understanding of how these therapies impact both tumor cells and cells within the tumor microenvironment. Interactions between tumor cells and the tumor microenvironment are critical for tumor growth, progression, and response to therapy.