At least two subpopulations of activated macrophages coexist
At least two subpopulations of activated macrophages coexist in a tumor microenvironment. The first subpopulation is the classically activated macrophages (i.e., M1 macrophages), characterized by the IL-12high, -23high, and -10low phenotypes; these macrophages can produce TNF-α and nitric oxide. The M1 macrophages are traditionally regarded as potent effector cells that can destroy microorganisms and tumor cells. The other subpopulation is termed alternatively as “activated macrophages” (i.e., M2 macrophages). Exposure to IL-4, -13, vitamin D3, glucocorticoids, or TGF-β decreases the antigen-presenting capability of macrophages and upregulates the expression of macrophage mannose receptors (MMR; also known as CD206), scavenger receptors (SR-A; also known as CD204), CD163, dectin-1, and DC-SIGN. The M2 macrophages are characterized by the IL-12low, -23low, and -10high phenotypes and are involved in stromal formation, tissue repair, tumor growth, angiogenesis, lymphangiogenesis, and immunosuppression. Whether TAMs proliferate in human tumors and to what extent remain to be elucidated. However, the consensus is that M2 TAMs have an instrumental role in promoting distant metastases and immune regulation at the primary tumor site.
Furthermore, CAFs have a major role in chronic inflammation; CAFs represent a crucial source of tumor-promoting cytokines and growth factors and express a proinflammatory gene signature in skin, breast, and pancreatic cancers, which is regulated by nuclear factor kappa-light-chain-enhancer of activated H 89 (NF-κB). The CAFs are believed to originate from mesenchymal stem cells. However, recent data suggest that other bone marrow cells can also regulate their activity. For instance, in murine models of breast cancer, endocrinal signals originating in cancer cells can mobilize Sca + cKit− granulin+ bone marrow cells. These cells do not directly promote tumor growth, but they act on the local fibroblasts in the tumor microenvironment to convert their phenotype into a cancer-promoting phenotype. The granulin-induced genes in CAFs include various chemokines, cytokines, and matrix-remodeling factors that are already implicated in tumor promotion. In human breast cancer, increased granulin expression is reportedly correlated with aggressive, triple-negative, basal-like tumor cells, and reduced patient survival. This is another example of cell cooperation in cancer inflammation. A recent paper highlighted the importance of fibroblasts in the tumor microenvironment; on the depletion of fibroblasts that express fibroblast activation protein-α in tumor-bearing mice, rapid hypoxic necrosis of the tumor and stromal cells occurred with IFN-γ- and TNF-α-mediated CD8+ T cell cytotoxicity.
Current treatment of cancer-related fatigue Cancer-related fatigue is a major clinical concern: well-controlled CRF can improve the QOL of cancer patients and their willingness to accept further cancer treatments. However, CRF is a common symptom that is distressing to patients and often difficult to treat. Despite the role of drug treatment in CRF management, no consensus has been reached regarding which drugs are useful. A further understanding of the recommendations for drug treatment requires knowledge of the classification of recommendations and the levels of evidence system that have been assigned by the NCCN guidelines. A review of the study outcomes reveals that therapeutic drug classes such as methylphenidate or hematopoietic agents, corticosteroids, psychostimulants, antidepressants, and l-carnitine may confer beneficial effects on CRF. These recommendations are based on multiple clinical trials and are relevant to the size of the population studied.
Targeting cancer-related inflammation: immune modulators and traditional Chinese medicine for the treatment of CRF The field of Traditional Chinese Medicine recognizes CRF as a deficiency pattern, which is primarily caused by deficiency of both qi and blood and disharmony of yin and yang and blood stasis. Traditional Chinese medicines have potential beneficial effects in treating cancer, suppressing cancer progression, improving the immune system, and ameliorating chemotherapy-induced or radiotherapy-induced complications and adverse effects such as pain and fatigue. Furthermore, increasing evidence suggests that certain TCMs such as Coptis chinensis (Huang lian), Scutellaria baicalensis (Huang qin), Camellia sinensis (Lu cha), Wedelia chinensis (Peng qi ju), and Songyou Yin (a Chinese herbal compound), contain abundant phytochemicals, and may reverse the epithelial–mesenchymal transition and reduce metastasis. Thus, these herbs may be useful as complementary and alternative treatments and/or as adjuvant therapy for conventional cytotoxic therapies.