Tumor tissues are composed of two major compartments: the malignant cancer cells and the tumor microenvironment. The second is a complex system that includes different non-tumor cell populations such as endothelial cells, lymphocytes, macrophages, dendritic cells, fibroblasts and pericytes; and of released factors including growth factors, cytokines, proteases and extracellular matrix. Emerging evidence has indicated that stromal cells within the tumor microenvironment, educated by the presence of malignant tumor cells, undergo phenotypic and epigenetic changes during tumor initiation, progression and metastasis. Conversely, stromal cells within the tumor microenvironment may provide signals to facilitate tumor cell proliferation, survival, migration and invasion, and mediate tumor cell response to anticancer therapies. This cross-talk between tumor cells and the tumor microenvironment can happen at different stages of cancer development and play an important role during cancer initiation and progression. Besides the local tumor microenvironment, recent work has suggested that primary tumors communicate with tissue parenchyma at distant organs to induce the formation of a premetastatic microenvironment that facilitates colonization and outgrowth of metastatic tumor cells. The following sections summarize recent findings on major characters of both local tumor microenvironment and the premetastatic microenvironment, and how these characters influence tumor growth and metastasis.
The local tumor microenvironment
The formation of new blood vessels from existing ones, a process termed angiogenesis, is a hallmark of cancer and an important process in the tumor microenvironment. New-born tumors cannot grow beyond certain limits (1 to 3 mm) and become dormant without the development of tumor vasculature. During angiogenesis, endothelial cells undergo extensive cell proliferation, migration and differentiation with help from accessory cells. All these processes are tightly controlled by a balance of angiogenic factors (VEGF, FGFs, angiopoietin-1, etc) and inhibitors (TSP-1, angiostatin, etc). Multiple proangiogenic factors including VEGF and bFGF are usually found upregulated within the tumor microenvironment and associated with tumor progression. VEGF and bFGF, through binding to their cognate receptors on endothelial cells, activate the downstream signaling pathways such as MAPK, Akt, Src and Stat3 and regulate endothelial cell function like cell proliferation, survival, migration and invasion.
The presence of leukocytes in tumor tissues, observed by Rudolf Virchow nearly two hundred years ago, provided the first indication of a possible link between inflammation and cancer. Today, results from epidemiological and genetic studies have revealed a firm yet complicated connection between chronic inflammation and different forms of cancer. Inflammatory conditions can initiate or promote oncogenic transformation, and genetic and epigenetic changes in malignant cells can also generate an inflammatory microenvironment that supports tumor progression.
Cancer-related inflammation is characterized by the presence of inflammatory cells and mediators such as chemokines and cytokines. Macrophages, an essential component of innate immunity against infection, represent a major cell population among inflammatory cells that infiltrate tumor tissues and dominate cancer-related inflammation. The presence of tumor-associated macrophages (TAMs) has been associated with tumor recurrence and poor prognosis in patients with different tumor types. Phenotypic characterization of TAMs demonstrates that these cells resemble the M2-polarized macrophages, marked by impaired ex
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Two transcription factors, NF-κB and Stat3, have been identified as key factors in regulation of cancer-related inflammation. NF-κB induces ex
The immunosuppressive tumor microenvironment
It has been well established that solid tumors evolve mechanisms to escape immune surveillance by creating an immunosuppressive tumor microenvironment through a process called immune editing. These include alterations of components of the antigen presentation machinery, secretion of immunosuppressive factors and recruitment of regulatory cell populations. All these mechanisms may cooperate in advanced stages of cancer to render tumor cells resistance to immune system and limit the effectiveness of immunotherapy against cancer.
One well-understood mechanism used by tumors to avoid T cell-mediated destruction is to compromise antigen presentation by dendritic cells (DCs). DCs are professional antigen presenting cells (APCs) that recognize, process and present antigens to naïve T cells for the induction of antigen-specific immune responses. Tumor cells secret immunosuppressive cytokines such as VEGF, IL-10 and TGF-β that inhibit maturation of DCs and increase accumulation of immature DCs that induce T cell tolerance. CD11b+Gr1+ myeloid derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells composed of immature myeloid cells, granulocytes, and monocytes. MDSCs have been shown to accumulate in the tumor microenvironment and inhibit function of a variety of immune cells that are important components in the antitumor immunity including CD8+ T cells, NK cells and dendritic cells. CD4+CD25+Foxp3+ regulatory T cells play a crucial role in maintaining immune homeostasis under physiological conditions. Recent studies have demonstrated that immunosuppression mediated by Tregs is one of the most critical mechanisms of tumor immune escape and a major hurdle for successful tumor immunotherapy. Through secretion of immunosuppressive cytokines, such as IL-10 and TGF-β, tumor cells can prevent the induction of antitumor immunity through the expansion and recruitment of Tregs.
The premetastatic microenvironment
Metastasis is a complex multistep event in which malignant cells spread from the primary tumor to distant organs and remains the leading cause of death in cancer patients. The process of metastasis involves tumor cell invasion into the surrounding stroma in the primary tumor, intravasation, and survival in the circulation, extravasation and outgrowth at the target organ. Although tumor cells have been the driving force of metastasis, it has long been accepted that the interaction between tumor cells and their surrounding environment is crucial for each step of the metastatic process. In 1889, Stephen Paget proposed the “seeds and soils” hypothesis in the study of cancer metastasis. Metastatic tumor cells, the “seeds”, can only grow at the secondary sites with a permissive microenvironment (soils). The hypothesis is consistent with the clinical observations that solid tumors have different preferences in developing site specific metastasis.
The “seeds and soils” hypothesis of Stephen Paget is largely extended by the recent discovery of the premetastatic niche at target sites of metastasis before arrival of tumor cells. Kaplan and his colleagues demonstrated that VEGFR1+ bone marrow-derived haematopoietic progenitor cells (HPCs) are recruited to the premetastatic organs before the arrival of tumor cells to initiate the formation of the premetastatic niche. Blockade of VEGFR1 prevented niche formation and tumor metastasis. Since then, multiple lineages of bone marrow-derived cells (CD11+ myeloid cells, Ly-6G+Ly-6C+ granulocytes and MDSCs) have been shown, by several groups, to home to the premetastatic organs and participate in the formation of the premetastatic microenvironment. The mechanisms by which these bone marrow-derived cells are recruited to the premetastatic organs have been also illustrated. Kaplan et al showed that ex
Together, these findings have validated the importance of the key elements of the premetastatic microenvironment in directing tumor cell metastasis. Given that drugs that directly target metastatic tumor cells show only limited effects in treating metastatic diseases, it is desirable to develop therapeutics that target not only primary tumor sites but also the premetastatic microenvironment at distant organs to efficiently prevent and inhibit cancer metastasis.