Invasion Microenvironment Proteins

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 Invasion Microenvironment Proteins Background

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
Tumor angiogenesis
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.

Cancer-related inflammation
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 expression of M1-related genes, deficient antigen presentation and less tumoricidal activity, and high expression of M2-related genes and proangiogenic factors. Accordingly, TAMs have been shown to promote tumor growth by stimulating tumor angiogenesis and suppressing the antitumor immune responses.
In response to expression of cytokines and chemokines in the inflammatory microenvironment of tumors, T lymphocytes can also infiltrate tumor tissues. Mature T lymphocytes can be mainly categorized into two major populations according to their effector function: CD8+ cytotoxic T cells and CD4+ helper T cells, which include Th1, Th2, Th17 and regulatory T cells (Tregs). T cells can have both tumor-suppressing and promoting functions. Cytotoxic CD8+ T cells and Th1 cells have been shown to correlate with better survival rates in cancer patients. In contrast, some T cell subsets including Th2, Th17, and Tregs have been shown to promote tumor growth and metastasis. Similar to TAMs, the balance between tumor-supporting and suppressing T cells is regulated by the tumor microenvironment.
Two transcription factors, NF-κB and Stat3, have been identified as key factors in regulation of cancer-related inflammation. NF-κB induces expression of inflammatory cytokines, adhesion molecules, proangiogenic factors and key enzymes in the syntheses of nitric oxide and prostaglandin from tumor cells and inflammatory cells. In addition, NF-κB promotes tumor cell survival by upregulation of anti-apoptotic genes. Along with NF-κB, Stat3 is a point of convergence for numerous oncogenic signaling pathways. Aberrant activation of Stat3 in tumor cells and myeloid cells induces a large number of genes (IL-1β, IL-6, COX-2, etc) that are crucial for inflammation. Moreover, binding of these pro-inflammatory cytokines to their receptors further activates Stat3, forming a positive feedback loop between tumor cells and immune cells that boosts inflammatory responses in the tumor microenvironment. Recently, it has been shown that persistent activation of NF-κB in tumor cells and myeloid cells in the tumor microenvironment requires continuous Stat3 signaling.

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 expression of fibronectin was increased in the premetastatic lung, through which mediates the accumulation of VEGFR1+ HPCs. Hiratsuka et al. reported that VEGF, TGF-β and TNF-α released by primary tumors induced the expression of chemotactic factors such as S100A8 and S100A9 in the premetastatic lung, which triggered infiltration of CD11b+ cells and later metastatic tumor cells. Moreover, it has been shown that lysyl oxidase (LOX), induced by the hypoxic tumor microenvironment, colocalized with fibronectin at future sites of metastasis where it serves to crosslink collagen IV, which leads to increased adherence of CD11b+ myeloid cells and tumor metastasis. Furthermore, Kim et al. characterized the inflammatory responses in the premetastatic microenvironment and found that upregulated expression of a component of the extracellular matrix, versican, by the primary tumor induces proinflammatory cytokines such as TNF-α and IL-6 through activation of the Toll-like receptors in macrophages in the premetastatic microenvironment. It has also been shown that G-CSF, released by primary tumors, stimulates BV8 expression and mobilizes Ly-6G+Ly-6C+ granulocytes to the premetastatic microenvironment. Recently, it has been suggested that tumor-derived exosomes can contribute to the formation of metastatic niche, in a process dependent on CD44v6. 
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.