Introduction
Tumor-associated macrophages (TAMs) are a major cellular component of both mouse and human tumors (Pollard, 2004;
Lewis and Pollard, 2006). High numbers of TAMs in human tumors usually correlate with reduced patient survival (Bingle et al., 2002; Zhang et al., 2012), and studies in mice have shown that TAMs promote important steps in tumor progression including tumor angiogenesis, cancer cell invasion, metastasis, and the suppression of adaptive anti-tumor immunity (Noy and
Pollard, 2014). TAMs also mediate or limit the efficacy of various forms of anti-cancer therapies (De Palma and Lewis, 2013).
Recent fate-mapping experiments have shown that macrophages in steady-state tissues can originate from at least three
different
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Moreover, TAM distribution can vary between different types of tumor, and between primary or metastatic tumors (Lewis and Pollard, 2006). Importantly, across several types of human tumor, the abundance of a distinct subset of PV macrophages has been shown to correlate with increased tumor angiogenesis, distant metastasis, poor prognosis, and/or the recurrence of tumors after chemotherapy in various forms of cancer (Kurahara et al., 2012; Matsubara et al., 2013; Robinson et al., 2009).
As discussed in later sections, the markers expressed by PV macrophages vary between primary and metastatic tumors.
However, a unifying feature is their proximity to blood vessels
(sometimes making direct contact with endothelial cells or pericytes), or their preference for highly vascularized tumor areas.
This contrasts with the majority of TAMs found elsewhere in tumors
(Lewis and Pollard, 2006). This review discusses recent studies demonstrating an array of tumor-promoting functions for PV macrophages in both primary and secondary tumors
(summarized in Figure 1).
Tumor Angiogenesis
A distinct subset of PV TAMs has been shown to regulate angiogenesis in various mouse primary tumor models and to correlate with microvessel density in human tumors. BM transplant experiments conducted by De Palma et al. (2003, 2005) identified a subset of BM-derived TAMs that cluster around tumor blood vessels and express higher levels of the angiopoietin receptor,
TIE2, and the mannose receptor,
Several studies have shown the microenvironment and ECM are reservoirs of cellular and non-cellular materials, which help, modulate growth, survival, motility and invasive behaviour (LR)(Maeda et al., 2004). Hence studies on tumour epithelial cells and their niche are of current interest, as these interactions with regards to tumorigenesis have not fully been
The uncontrollable spread of cancer is the principal event which leads to the death in individuals with cancer and it is the greatest barrier of developing cures for cancer. Metastasis is the progressive spread of malignant cancer cells from the primary tumour to secondary organ in distant sites and this potential is dependent on the specific microenvironment which support them to complete each step of the metastatic process (Poste & Fidler 1980). To understand the molecular basis of metastasis, investigators have now separated the complex and highly selective metastasis process into series of steps to try and solve the problems cause by
The principal mechanism leading to pain and inflammation is the arachidonic acid (AA) pathway. AA is typically bound to the membrane phospholipids and is released by a group of enzymes known as the phospholipases A2’s. AA acts as the precursor of the group of bioactive lipids collectively known as the eisosanoids. There have been several reports that AA and the eicosanoids are intimately linked to cancer biology (Markaverich et al., 2007; Nie et al., 2001; Pan et al., 2008; Sveinbjornsson et al., 2008). The downstream enzymatic pathways of AA, the cycloxygenases (COX) and the lipoxygenase (LOX) pathways, are responsible for the synthesis of the eicosanoids from AA. Elevated levels of the COX-2 protein have been reported in archived breast cancer tissue, and studies indicate that the overexpression of COX-2 is sufficient to induce mammary tumor formation in transgenic mice (Denkert et al., 2004; Liu et al., 2001). Human cancerous breast tissue indicates 3- to 30-fold higher 12-LO mRNA when compared to the normal breast tissue (Ding et al., 2003; Natarajan et al., 1997). There is sufficient evidence that the products of the COX and LOX enzymatic pathways, the eicosanoids, such as the prostaglandin (PG) PGE2 and
Cancer has been a disease since the dawn of man and even since that moment, we as humans have strived to understand its’ lethality and discover ways to combat it. This proves to be a more difficult task than it seems. Cancer, by definition, is the uncontrolled division of abnormal cells in the body [1]. These divisions can spread into the surrounding tissues as well and cause damage to the regions they locate to. Many of these divisions can lead to solid growths in the body. The growths are usually referred to as tumors [1]. These tumors are masses of tissue that group together.
CVD [27]. In this response, macrophages play an important role, through the production of proinflammatory
The complement protein C3 binds to the cell wall and increases the recognition of Mycobacterium by macrophages. After macrophages have been absorbed, Mycobacterium proliferates slowly through bacterial cell division, which occurs every 25 to 32 hours. Macrophages release proteolytic enzymes and cytokines to break down the bacteria. Macrophages then present Mycobacterium antigens on the surface of T cells. This initiates an immune response that lasts for 2 to 12 weeks; the microorganisms continue to grow until they form enough numbers to fully induce the cell-mediated immune
The macrophage is one of the white cells. From the white blood cell called monocytes, the macrophages are produced. It is a cell responsible for engulfing, digesting a cellular debris and is able to locate the foreign substances and cancer cells. In order to get rid of the unwanted invaders the phagocytosis destroys and cleans the body. The macrophage is aware of which cell is to keep and which do not belong to the body.
More evidence demonstrates that tumor microenvironment has played a role in tumor outgrowth and progression. Multiple host defense systems, including host immune system, constantly fight against the invader, and their efficacy is directly associated with the disease outcomes. To understand the molecular mechanism of viral-host interaction
CN’s dimeric structure results in high reactivity in platelet protein phosphorylation, allowing CN to bind to IIb3 and inhibiting platelet aggregation. It is also known that CN is able to bind to 1 and 3 subclasses, inhibiting many types of integrins (Lin et al. 2010). Research has shown that the two integrins that are expressed in angiogenesis and cancer metastasis are v3 and v5. Blocking v5 results in blocking the vascular endothelial growth factor, or VEGF, angiogenesis because of its involvement in cell adhesion. This integrin requires an insulin growth factor to activate to mediate cell migration. Zhou et al. (2000) has shown that CN binding to vitronectin receptors allows the inhibition of melanoma and breast cancer cells to vitronectin. In addition, v3 commonly mediates tumor cell adhesion to vitronectin. However, antagonists to this integrin can inhibit angiogenesis in endothelial cells, with CN acting as an antagonist. Many studies have tested the efficacy of CN on tumors from breast cancer, prostate cancer, and bladder cancer. For example, CN was able to inhibit the adhesion of T24 bladder carcinoma cells to vitronectin (Zhou et
Cancer is a group of 200 or more diseases of controlled cell growth. The treatment of cancer can be very difficult process. Breast Cancer is most prevalent form of cancer among women and second leading cause of death. From a clinical standpoint radiation chemotherapy not only made strides in preventing the reoccurrence in cancer but also has some side effects that needed to be treated in order for a women to return to a healthy lifestyle. For example chemotherapy cause substantial weight loss, diaria, vomiting, anorexia and nausea after chemotherapy. The person may develop anemia, skin disorders, be sun sensitivity and become more vulnerable to every day common infections. The person will most likely lose their hair and substantially loss
George Mackaness coined the concept of macrophage resistance and activation in the beginning of the 20th century. He showed that the “inactivation” of macrophages had a lot to do with the pathogen-host interaction. In other words, substances in their respective microenvironments could influence macrophages to attain a particular phenotype (7). This eventually becomes significant when studying cancer and the microenvironment associated with it. One of the most important milestones in the study of macrophages was the their identification as sources of cytokines.
Tumor angiogenesis refers to an attribute of tumor cells residing with the capacity to elicit continuously the growth of new capillary endothelium. Tumor angiogenesis occurs by recruitment of endothelial cell precursor or by sprouting of existing capillaries as in physiologic angiogenesis. Angiogenesis (the formation of new blood vessels) is implicated in the pathogenesis of many chronic diseases including cancer. Angiogenesis in the tumor mass permits growth and invasiveness of the cancer cells as it is believed to be essential for the delivery of essential nutrients and oxygen to the tumor microenvironment. Clustered evidence suggests that angiogenesis is a critical event in the progression of solid tumors because tumor growth beyond 2 to
Therefore, patients can receive treatment before cancer metastasizes to other areas of the body, which is resulting in better health outcomes. The main challenge in circulating tumor cell (CTC) research is their detection, which requires the ability to detect one CTC out of almost 1 billion normal blood cells [2, 3]. Based on the known properties of tumor cells, several platforms for CTC detection have been developed. Such platforms can be classified into two major categories: (I) Immunochemistry-based methods, and (II) physical property-based methods. CELLSEARCHTM from Janssen Diagnostics is considered the most successful and the only FDA-approved platform for CTC detection in clinical practice in patients with breast, prostate, and colorectal cancers. Limitation of this method is the low yield of CTC capture from larger blood volume. Metastasis often involves epithelial-to-mesenchymal transition (EMT) of cells; thus, epithelial marker-dependent approaches may miss numerous CTCs that have low or absent epithelial marker expression. Isolation by size of epithelial tumor cells (ISET) [4] is another widely accepted size-based approach. This platform applies a specific membrane filter for tumor cell selection, because tumor cells are often larger and stiffer than blood cells. Main advantage of using membrane filter is that cells can be retained for further investigation. Nonetheless, the sizes of tumor cells may vary
Today, close to 120 years after Dr. Coley’s findings, cancer immune therapies have come to the forefront of therapeutic interventions of cancer (Couzin-Frankel, 2013).
Inflammation is generally an acute process that occurs in response to infection and tissue damage. This protective mechanism involves members of the innate immune system such as macrophages and neutrophils recognizing pathogen-associated molecular patterns (PAMPS) as well as damage-associated molecular patterns (DAMPs) and initiating mediators that increase vasodilation, edema and pain. Long-term inflammation can also occur and leads to a chronic state with conditions favorable for tissue damage and genomic lesions (1,2). Over time this genetic damage can lead to cancer. An example of chronic inflammation leading to cancer development can be seen in patients with ulcerative colitis.