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this lncRNA in the formation of paraspeckles. Another their exit from the capillaries (extravasation). Extravasation
[29]
lncRNA that provides a platform for the binding of protein is is primarily supported by enhanced permeability of
telomerase RNA (TER). TER along with telomerase reverse capillary. Vascular endothelial growth factor secreted by
transcriptase (TERT) is essential for telomere synthesis. A tumor cells can increase the permeability of blood vessels.
telomere is nucleotide repeat at the end of DNA which is In addition, other factors such as alterations in receptor
required for the genomic stability. TER is a template RNA expression and physical bursting may also help in the exit
[30]
for the synthesis of telomere. TER consists of various of tumor cells from blood vessels. [42]
[31]
motifs; core domain is essential for template activity and
CR4/CR5 domain binds with TERT. The mutation in Once the cells depart the capillary, they try to colonize in
[32]
core domain of TER disintegrates proper structure of this distant organs. However, few of circulating tumor cells can
RNA, losing the binding capability to TERT, which leads colonize to establish micro-metastases. The colonization
to aplastic anemia. This indicates that a comprehensive is dictated by the microenvironment of primary site and
[33]
structure of TER functions as a scaffold for telomerase to distant site. A number of cytokines both from tumors and
bind and work properly. the site of colonization provide mitogenic signals for the
successful proliferation, survival and resist to apoptosis in
CANCER METASTASIS IS A MULTISTEP alien environment, finally to develop macro-metastases. [43]
PROCESS
LNCRNAS AND CANCER METASTASIS
More than 90% of cancer death is attributed to metastasis.
Cancer metastasis is a process in which cancer cells migrate In the previous section, we highlighted the steps during
from its origin to a distant site and then proliferate. The two metastasis. Several genetic and epigenetic modifications
major steps of metastasis are physical dissociation from the during this multistep process make cells sturdy to survive
origin of the primary tumor and migration to distant sites and the foreign ambience. Although we still do not have a clear
colonization of those migrating cells in the distant sites. [34] picture as to what causes those change, increasing evidence
suggests that lncRNAs play a crucial role in different stages
This multistep process is usually inefficient and only very of metastasis [Figure 1]. We list the following lncRNAs as
few cells that start migrating from the origin would be examples.
able to colonize in distant organs. The disaggregation of Metastasis-associated lung adenocarcinoma
cells from the primary tumor is the first event during the transcript 1
metastasis. This process is greatly enhanced by loss of
E-cadherin, a protein, that helps to adhere epithelial cells Metastasis-associated lung adenocarcinoma transcript 1
together. [35,36] The next barrier that prevents migration of the (MALAT1) is located at chromosome 11q13 with 8.7 kb
cancer cell is basement membrane. The disintegrated cancer in length. It is expressed in most tissues with the highest
cells can induce stroma to secrete proteolytic enzyme-like level in pancreas and lung. The elevated expression of
matrix metalloproteinases that dissolve the basal lamina. MALAT1 was found in metastatic cases of non-small cell
[37]
Detached cells also require motility to move from one place lung carcinoma, and as such, it was named MALAT1. The
to another. Several changes in cytoskeleton, interactions high expression of MALAT1 in metastatic tumors predicts
between cell and matrix, and induced Rho, cdc42, and poor prognosis. As a nuclear lncRNA, MALAT1 plays an
[44]
Rac signaling are important for mobility. Furthermore, important role in alternative splicing. However, loss of
[45]
epithelial-mesenchymal transition (EMT) is critical for MALAT1 does not seem to affect alternative splicing in the
dissemination of the cancer cell to distant site as it helps lung cancer tissue; rather it affects expression of different
in effective motility and invasiveness and survival of the genes, including those involved in EMT (LPHN2, ABC1)
cells. To reach the distant organs, the cells also require a and others in regulation of metastasis formation (GPC6,
[38]
traveling path. The hematogenous route works as highway MCAM, PRCKE). Furthermore, tail vein injection of
for this process. Although it is still unclear how the xenograft mice with A549 cells overexpressing MALAT1
[39]
altered cells invade into the blood vessels, the high invasive shows diffused growth in the lung. Knockdown of MALAT1
capacity of metastasizing cells and chemoattractive factors results in either fewer tumor nodules or the cells cannot exit
in the blood may help their intravasation. Inside the blood out of endothelial cells. Similarly, loss of MALAT1 in
[46]
vessels, the migrating cells endure a constant physical A549 cells inhibits expression of those genes (CTHRC1,
pressure as well as immune responses, an inclement CCT4, HMMR) that regulate folding of cytoskeleton and
condition for tumor cells. However, the chance of survival migration of cells. These lines of evidence indicate that
[47]
can be increased by adhering tumor cells to different factors MALAT1 is critically important for the cell motility and
such as thrombin. Tumor cells may also be able to attach extravasation of cells from capillaries.
[40]
to endothelial cells via protein-protein interaction (integrin
α3β1 of tumor and laminin 5 of endothelial cells) to protect In addition to lung cancer, MALAT1 is also important for
themselves from harsh condition. The adherence of cells pancreatic and cervical cancer metastasis. In pancreatic
[41]
[48]
not only prevent their possible elimination, but also help cancer, MALAT1 enhances expression of EMT markers
4
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 1 ¦ January 15, 2016 ¦