The duration of metastatic latency varies between cancer types, and for the most aggressive ones it is very short, resulting in high relapse and mortality rates following diagnosis. In lung cancer, the metastatic latency interval usually lasts only a few weeks. In this type of cancer, malignant cells acquire metastatic traits for rapid and massive cell dissemination, followed by colonization of multiple secondary organs. The short latency in lung cancer implies that malignant cells in the primary tumor acquire most of the metastatic traits, thus enabling them to overtake organs immediately after arrival. In contrast, a well-known example of a tumor type with very long latency is prostate cancer. Similarly, some of the breast cancer metastasis may also remain dormant only to present with widespread metastasis years and even decades later.22
THE METASTATIC NICHE AND FORMATION OF MACROMETASTASIS
DTCs need time to alter or unleash the required functions for tumor initiation and expansion in the secondary site. For the successful establishment of a metastasis several crucial events must take place, the most important among which are cell cycle activity and angiogenesis. It is obvious then that there are intrinsic differences in genomic makeup of tumor cells that must be evaluated to understand the factors intrinsic to the cell (seed). However, it is equally important to acknowledge the microenvironmental condition of the host tissue, the soil that plays a key role in the acquisition of proliferative phenotype by the tumor cells.
Studies using, radioactive labeling of the injected cancer cells showed that they were equally likely to be trapped in a variety of tissue.18 So, just landing in a tissue is not enough for cancer cells to develop a secondary tumor; rather, some role of the tissue itself may be crucial in sustaining the new growth. The findings of Tarin et al23 that the development of secondary cancer was rare even upon direct deposition of millions of tumor cells into the vena cava (to reduce ascites from ovarian cancer) is a good indication of the importance of other factors involved.
In stem cell biology the specialized microenvironment that supports stem cell maintenance and actively regulates cell function and proliferation is termed as niche.24 A similar model has been suggested to delineate the interactions of malignant cells with their microenvironment at metastatic sites. This microenvironment comprises supportive non-neoplastic stromal cells, soluble factors, vascular networks, nutrients and metabolic components, and the structural extracellular matrix architecture. Although the precise genetic makeup of a cell is undoubtedly pivotal in determining its malignant phenotype, the metastatic niche model stipulates that microenvironmental factors are also important in permitting malignant cells to realize their metastatic potential. Thus, with the right genetic makeup of the tumor cells accompanied by a permissive and supportive environment in the host organ, the tumor cells may proliferate and ultimately develop into a clinically detectable macrometastasis. The metastatic niche model suggests that a suitably conducive microenvironment must evolve for tumor cells to be able to engraft and proliferate at secondary sites with the transition from micrometastatic to macrometastatic status.25 The idea that cancer cells require some nourishment and support from their environment to develop is an important focus of research today, with the aim of unraveling the molecular mechanisms that bring seed and soil together to promote metastasis.
THE CONCEPT OF PREMETASTATIC NICHE
The premetastatic niche can be defined as a supportive and receptive tissue microenvironment undergoing a series of molecular and cellular changes to form the metastatic-designated sites, prior to the arrival of the metastatic tumor. Dr Lyden and colleagues pioneered the research on the premetastatic niche and the role and significance of the premetastatic niche in metastasis has attracted more and more attention in recent years.26 Their landmark study was the first demonstration of a microenvironment designed to attract tumor cells to a target organ and set the stage for future work to discover additional factors that contribute to premetastatic niche formation.
The process of premetastatic niche formation in distant organs is initiated by the primary tumor that produces tumor-derived secreted factors prior to tumor dissemination.27 These factors include vascular endothelial growth factor (VEGF-A) and placental growth factor among others. These factors increase the proliferation of fibroblast-like stromal cells, which contribute to local deposition of fibronectin. Tumor-derived secreted factors promote premetastatic niche formation by mobilizing and recruiting VEGFR1+ bonemarrow-derived hematopoietic progenitor cells directly from the bone marrow to the premetastatic niche (Fig. 6). These cells express VLA−4 that binds to fibronectin and allows them to assemble at the site. Most notably, the VEGFR1+ niche cells act as harbingers of organ-specific carcinoma spread. Others, such as tumor necrosis factor alpha (TNF-a) and transforming growth factor b (TGF-b), along with VEGF-A, induce the expression of S100A8 and S100A9 in the lung to develop premetastatic niches.25–30
Premetastatic niche formation is facilitated in large part by the presence of a suppressed immune system. Primary tumors recruit myeloid cells, which are the precursors to immune cells. These cells enable the tumor cells to avoid detection by the immune system as they metastasize, and thus allow the metastasis to flourish. Once the primary tumors have entered the bloodstream, myeloid cells that have been recruited by the tumor protect the cancer cells from detection by the immune system, which would otherwise be more likely to be effective in halting metastasis. Myeloid progenitor cells, recruited at various stages in their cell cycle, are believed to constitute much of the premetastatic niche, as they can protect the tumor cells from the standard immune response as the cancer cells attempt to colonize the premetastatic niche. Given their important role in protecting the growing metastasis from immune system attacks, myeloid cells are a key factor in the development of the premetastatic niche, and thus eventually in promoting metastases.29,31
Chemokines, also play a significant role in the creation of premetastatic niches and metastases. The primary tumor, to evade detection by the immune system, uses chemokines to increase recruitment of bone marrow-derived myeloid cells to secondary organs. In addition, cancer cells from the primary tumor can be used to induce inflammation in the future site of the premetastatic niche in the secondary organ, which is like the immune response created by an infection. Thus, the large presence of immune cells allows the premetastatic niche to ward off attacks by the immune system and therefore allow the tumor to metastasize without inhibition.29,32
The formation of a premetastatic niche not only involves the recruitment of foreign cells, such as immune cells, but also the reprogramming of the resident stromal cells to facilitate metastatic growth. Normal lung fibroblasts express miR-30 family members to restrain MMPs, such as MMP9, to stabilize the lung vasculature. Cancer cells reprogram fibroblasts to decrease their expression of miR-30 family members, resulting in enhanced MMP activity, vascular permeability, and metastasis. Factors secreted from the primary tumor induce the expression of α-smooth muscle actin—in premetastatic fibroblasts, activating them to induce remodeling extracellular matrix through secretion of fibronectin, Lysyl Oxidases LOX and LOXL2, thereby generating a more permissive microenvironment for survival and outgrowth of DTC.28,29,33–35
Thus, immune suppression, combined with hypoxia and changes in extracellular matrix, among other processes, are essential steps in creating premetastatic niches that allow tumor cells to grow in a foreign and hostile environment without being destroyed by the typical response of the immune system.
ROLE OF EXOSOMES IN TUMOR METASTASIS
Exosomes are spherical to cup shaped, lipid bilayer membrane nanovesicles 40 to 100 nm in diameter. These vesicles are secreted by many cells and can be found in most body fluids such as urine and blood as well as in supernatants of cultured cells. Exosomes must be differentiated from other secreted cellular entities such as microvesicles (50 to 1000 nm in diameter) and ectosomes, which are microvesicles derived from neutrophils or monocytes and apoptotic bodies (500 to 2000 nm in diameter).36,37
Exosome formation is a fine-tuned process which includes 4 stages: initiation, endocytosis, multivesicular bodies formation, and exosome secretion. Multivesicular bodies are endocytic structures formed by the budding of an endosomal membrane into the lumen of the compartment (Fig. 7). After vesicular accumulation, the multivesicular bodies are either sorted for cargo degradation in the lysosome or released into the extracellular space as exosomes by fusing with the plasma membrane.38
In addition to lipids, nucleic acids, and proteins have also been detected in exosomes. The protein composition of tumor cell-derived exosomes has been well characterized for several cancers by using different proteomic methods. To date, 4563 proteins, 1639 mRNAs, and 764 miRNAs have been identified in exosomes from different species and tissues by independent examinations.39
The exosomes can transfer their constituentsand cargo to neighboring or distant cells with preservation of their function. Several mechanisms for the uptake of exosomes by recipient cells, such as exosome fusion with the membrane of the recipient cell, endocytosis by phagocytosis, and receptor-ligand interaction.40 Initially discovered as the garbage bags for removal of unwanted material from cells, the role of exosomes in immune response and cancer is gradually recognized. Exosomes are now considered important mediators in intercellular communication. The capability of exosomes to transfer proteins, DNA, mRNA, as well as non-coding RNAs has made them an attractive focus of research into the pathogenesis of different diseases, including cancer.40,41
It has been noted that cancer cells secrete much higher amounts of exosomes in comparison with nontransformed cells. These exosomes not only influence proximal tumor cells and stromal cells in local microenvironment, but also can exert systemic effects when participating in blood circulation. Exosomes have been shown to be implicated in the induction of apoptosis of cytotoxic T cells, expansion and function of regulatory T cells (Treg cells), induction of M2 polarization of macrophages, inhibition of cytotoxicity of natural killer cells, inhibition of differentiation of dendritic cells, expansion and activation of myeloid-derived suppressor cells and mobilization of neutrophils. Exosomes released under hypoxic conditions can stimulate angiogenesis through interactions with endothelial cells.
Exosomal transforming growth factor β (TGFβ) can induce differentiation of fibroblasts into tumor-supporting myofibroblasts and exosomes from ovarian cancer are able to convert adipose-derived mesenchymal stem cells into myofibroblast-like cells, supporting tumor growth and angiogenesis.36,41
As exosomes can transfer specific proteins and nucleic acids to recipient cells in the tumor microenvironment or at specific distant sites, cancers have used exosomes as a tool by which cancer cells can transfer malignant phenotype to normal cells and establish a fertile local and distant microenvironment to help cancer cell growth. Exosomes contribute to tumor metastasis by enhancing tumor cell migration and invasion, remodeling the extracellular matrix and establishing premetastatic niche.36,41–43
A better understanding of the mechanisms of metastatic disease in recent years seems to support the seed and soil theory proposed by Steven Pagets almost 130 years ago. Preventing metastasis in high-risk patients would be far better than having to treat it later. Recent recognition of the concept of the premetastatic niche allows researchers to consider several new possibilities for treating cancer.44 Research on the mechanisms that control and support the viability of latent metastatic cells should yield clues for targeting cancer with the goal of preventing metastasis. Factors from the primary tumor that structurally alter the secondary organ to facilitate its colonization by tumor cells could also potentially be targeted to stop metastasis. Recognition of the role of exosomes in tumor progression is also an important potential target for early detection of cancer and prevention of premetastatic niche formation.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
seed; soil; metastasis; exosomes; niche; premetastatic; macrophage; intravasation; extravasation; bone marrow