Within dendritic cells, several functional quite opposite acting cell populations are discerned; conventional DC will present tumor antigens to T lymphocytes and force the production of cytotoxic T cells, whereas plasmocytoid and monocytoid DCs act as tumor protective cells.
Another action to prevent cytotoxic lymphocyte attack is to induce an influx of regulatory T cells Treg. Treg downregulate the production and influx of cytotoxic T cells and NK cells and promote immune tolerance [ 50 — 52 ].
Finally, also bone marrow-derived myeloid precursor cells MDSCs may downregulate a T cell-based immune reaction towards growing tumor cells by secreting arginase I [ 53 ]. In addition, vascular density was significantly reduced in Ido1-nullizygous mice [ 54 ]. In some carcinomas, preferentially in pulmonary squamous cell carcinomas, eosinophils are found in abundance.
In one study, it was shown that ILE has antitumor activity. Injections of recombinant ILE resulted in significant antitumor activity.
Combining ILE with chemotherapy increased the antitumor efficacy in a xenograft model [ 55 ]. If eosinophils are directly acting cytotoxic against the tumor cells, for example, by releasing cytotoxic basic proteins was not explored in this study. After having established the primary tumor and organized nutrition as well as protection for immune cell attacks, the tumor cells have to acquire changes to migrate to distant sites and establish metastasis.
There are two different forms how tumor cells migrate, single-cell or small-cell cluster movement as it is seen in small-cell carcinoma as well as undifferentiated NSCLC and movement by large clusters of organized cells such as in acinar adenocarcinoma or some cases of squamous cell carcinoma Figs.
For single cell and small clusters, migration seems to be much easier since single cells can more easily adapt, for example, a spindle cell morphology, which enables better movement.
Lung adenocarcinomas with high smooth muscle actin gene ACTA2 expression showed significantly enhanced distant metastasis and unfavorable prognosis. ACTA2 downregulation remarkably impaired in vitro migration, invasion, clonogenicity, and transendothelial penetration of adenocarcinoma cells without affecting proliferation. Migration within the stroma requires several changes in tumor cells, one is formation of invadopodia. Tyrosine kinase substrate 5 Tks5 is a scaffolding protein necessary for the formation of invadopodia.
There are different isoforms, some of them short isoforms associated with reduced other long isoforms increased metastasis [ 57 — 59 ]. However, migration of tumor cells seems to be regulated by different genes, so probably, there is not a single mechanism for each tumor type, but more likely that tumor cells individually have adapted different mechanisms of migration protocols and used it during carcinogenesis.
If CPNE3 was knocked down, the metastatic abilities were inhibited in a mouse model. In another study, nestin protein expression significantly correlated with tumor size and lymph node metastasis in NSCLC and also poor survival in patients with adenocarcinoma.
Nestin inhibition by shRNA decreased proliferation, migration, invasion, and sphere formation in adenocarcinoma cells [ 61 ]. One of the major studied mechanisms of tumor cell migration is EMT, which again is seen in tumors with single-cell or small-cluster migration type Fig.
Tumor cell migration, a this small-cell neuroendocrine carcinoma moves in small-cell groups, whereas the adenocarcinoma b moves almost as single cell. Tumor cell migration, a this mixed small- and large-cell neuroendocrine carcinoma migrates as single- or small-cell clusters, whereas the small-cell neuroendocrine carcinoma in b migrates in small complexes in this very early stage; experimental mouse model slides provided by A.
Tumor cell migration, a a mucinous adenocarcinoma moves in larger-cell complexes along the alveolar walls, still using the supply by the alveolar septa and b an unusual 3D complex of squamous cells moving as spheroids. When looking up studies on EMT, a huge amount of published article can be found in databases.
The major surprise is that different genes are associated with EMT. And even when focusing on lung cancer studies, there are still different genes found to trigger EMT. Suppression of Twist expression in metastatic mammary carcinoma cells inhibits their ability to metastasize from the mammary gland to the lung. Ectopic expression of Twist resulted in loss of E-cadherin-mediated adhesion, activation of mesenchymal markers, and induction of cell motility, suggesting that Twist promotes EMT [ 62 ].
Twist expressed in lung adenocarcinoma cell lines with EGFR mutation showed increased cell mobility. By knockdown endogenous SARI in a human lung xenograft-mouse model, multiple lymph node metastases developed. In the study by Blaukovitsch, another pathway for EMT was shown; Snail and Twist were not involved in pulmonary sarcomatoid carcinomas but instead upregulation of c-Jun and consecutive overexpressions of Vimentin and Fascin were seen [ 66 ].
So far, nothing similar was investigated for bone metastasis by pulmonary carcinomas. So far, we have focused on single-cell and small-cluster migration. However, in surgical pathology routine, most well-differentiated carcinomas including lung carcinomas move in large cell clusters; for example, acinar adenocarcinomas will show nice structured acini deep within the stroma and even within blood vessels Fig.
The mechanisms how these tumor cells manage their coordinated movement by retaining their epithelial structure is almost unknown. These carcinomas do not undergo EMT. Recently, in an investigation using drosophila border cells as a model, the processes of migration of large-cell complexes were elucidated.
By RNAi silencing, conserved signaling transduction genes were knocked down to identify essential pathways for border cell migration. The following four genes associated with TGF-beta signaling were identified: Rack1 receptor of activated C kinase , brk brinker , mad mother against dpp , and sax saxophone.
Inhibition of Src activity by Rack1 may be important for border cell migration and cluster cohesion maintenance. Although this study focused on signaling pathways involved in collective migration during embryogenesis and organogenesis, these data could be the first step in understanding migration of carcinoma complex cancer metastasis [ 69 ].
Vascular invasion, a tumor cells are scattered in acinar complexes within the intima of this pulmonary artery and b large acinar and papillary adenocarcinoma complexes can be seen within these blood vessels, demonstrating the other example of invasion as large tumor cell complexes. Tumor cells orient themselves along adhesion molecules as expressed by matrix proteins, but in addition, they also sense for oxygen and most probably also orient themselves for higher oxygen tension [ 70 ].
Invasion into blood vessels is very similar to invasion into the stroma. Tumor cells have already learned to degrade proteins of the basal lamina at the epithelial border, and similar proteins form the matrix of small blood vessels.
Forming holes into the basal lamina of these blood vessels is therefore easily done, and tumor cells migrate into the intima. However, a new problem arises for tumor cells within the circulation, shear stress due to tumor cell deformation in small blood vessels and the problem with coagulation.
Shear stress is usually well tolerated by those tumor cells which underwent EMT. This is one of the reasons why a majority of tumor cells do not survive within the circulation [ 71 ]. With respect to coagulation, tumor cells on one hand have to avoid being trapped within a blood clot but on the other hand, will need a clot to slow down the speed of the blood stream, attach to the clot, and use it for extravasation [ 72 ].
Clot formation might be induced by tissue factor being produced and released by macrophages. Impairment of macrophage function decreased tumor cell survival without altering clot formation, demonstrating that the recruitment of functional macrophages was essential for tumor cell survival [ 73 ]. Another way how tumor cells might trigger clot formation has been demonstrated in mucinous adenocarcinomas.
Mucins secreted by the tumor cells induced platelet aggregation and furthermore interacted with L-selectin and platelet-derived P-selectin without thrombin generation [ 74 ].
This interaction already points to the next step, adherence to vascular walls for extravasation. Coming back to tumor cell trapping by blood clots, it seems that carcinoma cells require the assistance of macrophages and granulocytes for fibrinolysis. In a study of lung carcinomas, fibrinolytic components as tissue plasminogen activators t-PA and the inhibitors PAI-1 and PAI-2 were all negative in tumor cells, whereas urokinase-specific antibodies stained loosely packed tumor cells and macrophages.
In another study analyzing pulmonary adenocarcinomas, a positive correlation was found between Ets-1 and urokinase-type plasminogen activator u-PA expression [ 76 ]. Invasion into lymph vessels is easier than into blood vessels due to the tiny wall of the former. In addition, carcinoma cells might already enter the lymphatic stream by the interstitial channels of the lymph draining system. On the contrary, lymph vessels can easily be congested by tumor cells.
This can reverse the lymph flow, which might explain unusual sites of lymph node metastasis and so-called skip lesions. In contrast to the situation within blood vessels, carcinoma cells in lymphatics have to deal with the immune system.
So, survival is dependent on induction of immune cell escape mechanisms see above. Whereas carcinoma cells entering the blood stream might early onset distant metastasis and thus shorten overall survival of the patient [ 1 ], propagation of carcinoma cells along the lymphatics will set distant metastasis later. These tumor cells will set primarily metastasis within regional lymph nodes. Carcinoma cells have to escape the circulation. However, the process how tumor cells select their final destination is still not clear.
A lot of information was gained from studies on homing mechanisms of lymphocytes and extravasation of granulocytes. The most important site are venules with high endothelia. First of all, the blood flow is reduced, which enables tumor cells to roll over the endothelia and express adhesion molecules. These adhesion molecules need to find their respective and specific receptors for adhesion.
Once adhering to the endothelia, tumor cells have to activate the coagulation system for better and firm adherence, followed by production of holes between endothelia for migration out of the vessel lumen. Several factors have been identified, such as caveolin, which increases cell permeability.
Loss of caveolin results in increased phosphorylation of VEGFR-2 and decreased association with the adherence junction protein, VE-cadherin. Loss of caveolin increases endothelial permeability and tumor growth [ 77 ]. Tumor cells might use different selectins such as E-selectin and P-selectin to adhere to specific sites on the endothelia of venules. Also, other selectins might be used, as has been shown by knockout of these selectins. By intravital microscopy, SCLC cells were shown to roll along vessel walls mimicking leukocyte behavior [ 78 ].
It is well known that few tumor cells survive within the circulation. Even more, from those tumor cells, which survive and finally leave the circulation and settle at a distant site, only a small proportion progress and form metastatic nodules [ 71 ]. Usually, single-tumor cells die probably with the exception of small-cell carcinoma cells , and small clusters form micronodules but do not grow further.
Another enigma is the selection of metastatic sites. In general, lung cancer cells prefer the brain, bones, adrenal glands, and within lung carcinoma types, small-cell neuroendocrine carcinomas as well as adenocarcinomas metastasize into the brain, whereas squamous cell carcinomas prefer bones.
What homing mechanisms are in action? And moreover, how carcinoma cells communicate with this new stroma? For example, in the brain, carcinoma cells need to organize their new homing by communicating with glial cells and also manipulate microglia to prevent attacks by immune cells and finally induce angiogenesis for their supply in nutrients and oxygen.
In the following paragraphs, we will focus on different aspects of homing, extravasation, and creation of a metastatic niche in different organs.
To leave the circulation, lung cancer cells need signals, which seem to be specific for each organ. Some of these, such as E-selectin, are used in several carcinomas including breast and lung. Systemic inflammation may increase the expression of E-selectin, which mediate lung metastasis of an experimental breast cancer model [ 79 ]. Hyperpermeability is also a factor important for homing, because this slows down the blood flow and enable rolling of the tumor cells over the endothelia.
Hyperpermeability is mediated by endothelial cell FAK, which upregulates E-selectin, leading to preferential homing of metastatic cancer cells to these foci [ 80 ].
Attachment of tumor cells however needs an activation of several other adhesion molecules. Once tumor cell attach on endothelia, they cause the induction of vascular cell adhesion molecule-1 VCAM-1 and vascular adhesion protein-1 VAP-1 , which is dependent on tumor cell-clot formation, induced by tissue coagulation factors [ 81 ].
Also, changes in the cell to cell junctions of endothelia are necessary for the tumor cells, to move through interendothelial gaps. This is facilitated by an overexpression of angiopoietin-2 [ 82 ]. In addition, also MD-2, a coreceptor for toll-like receptor 4, triggers the formation of regions of hyperpermeability in mice by upregulating C-C chemokine receptor type 2 CCR2 expression.
The group by Sadanandam identified 11 unique peptides specific for homing to lung, liver, bone marrow, or brain. Semaphorin 5A and its receptor plexin B3 were identified as relevant for homing to these organ sites [ 85 ]. A major factor for homing of carcinoma cells, including colon, lung, and breast, is the chemokine receptor CXCR4.
The unique function of CXCR4 is to promote the homing of tumor cells to their microenvironment at the distant organ sites [ 86 ]. CXCR4 inhibition reduced the influx of myeloid-derived cells and impaired lung metastases. CXCR4 is specifically expressed in stromal cells that prepare the protumor microenvironment [ 88 ].
Several other signaling proteins are also involved in metastatic homing and formation of a metastatic focus; however, how these different molecules interact with each other is not known. MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft. Angiogenesis at the metastatic site in one part follows the same principles as in the primary focus; however, there is one major problem. Whereas at the primary focus lung carcinoma cells cross-talk with stroma cells by mechanisms and transmitters which have been developed during the process of developing from the precursor lesion to in situ carcinoma to invasive carcinoma, this cross-talk is different in the new metastatic site.
Brain glial cells or bone marrow stroma cells might response to other signals than those stroma cells within the lung. So, the major developmental step to establish a metastatic focus is communication with the stroma, and further, more communication might be different depending on the location.
In one investigation, a bridge was built between angiogenesis at the primary and metastatic sites. CXCL12 was expressed in tumor cells and in tumor vessels; CXCR7 was expressed by tumor and endothelial cells in the primary tumor and in the brain metastasis.
CXCR4 showed a nuclear positivity in all samples, but only CXCL12 expression in tumor endothelial cells was significantly correlated with shorter survival [ 92 ]. In interaction with stroma, there are no published data which could highlight general mechanisms by which lung carcinoma cells communicate with their stromal counterparts; however, communication at different organ sites have been studied and therefore will be discussed in the following paragraph.
When discussing metastasis, many questions arise, which are still incompletely answered. When does metastasis occur? Is there a need for a certain size of the primary tumor that cells leave and start migrating? Moffitt Cancer Center is committed to the health and safety of our patients and their families. A secure website for patients to access their medical care at Moffitt. An online resource for referring physicians and their staff.
Our patient services specialists can assist you with scheduling an appointment, questions about medical records, insurance, billing and more. Patient Appointment Center Hours: 7 a. Monday - Friday; 8 a. What parts of the body does lung cancer spread to? Lung cancer can spread to almost any part of the body, but the most common locations for metastasis include the: Liver Bones Brain Adrenal glands Once cancerous cells make their way to other parts of the body, they can continue to reproduce, eventually forming secondary tumors.
How fast does lung cancer spread? Lung cancer — like any other type of cancer — usually does not spread right away. Metastasis is typically a gradual process, causing few if any side effects until the tumors become large enough to affect the nearby organs.
Metastatic lung cancers are usually stage 3 or stage 4, depending on how extensively the cancer has grown and spread. As cancerous cells accumulate in the lungs, they can slowly invade the healthy surrounding tissues. In most cases, they first spread to other parts of the lung.
This is known as local metastasis. However, if cancerous cells invade the lymph nodes, they can travel through the lymphatic system to other parts of the body, eventually forming secondary tumors in other organs.
This is known as distant metastasis. If you or a loved one has been diagnosed with metastatic lung cancer, you may have quite a few questions. Moffitt Cancer Center is here to help. The first consideration in choosing a systemic treatment is whether there are specific genetic changes in the primary lung tumor that may be targeted. If so, targeted therapy drugs designed to act on these gene changes would likely be the first choice. Chemotherapy, immunotherapy, or both, also may be options.
Because extensive-stage SCLC is cancer that has spread extensively in the body, systemic treatments such as chemotherapy or immunotherapy would be more useful than therapies such as radiation therapy or surgery that target a specific region of the body. As with stage 4 NSCLC, treatment would likely focus on blocking the cancer's growth, relieving symptoms and extending the patient's life.
Chemotherapy and immunotherapy, or a combination of both, are typically the first line of treatment at this stage. Patients with advanced lung cancer typically receive palliative care, whether alongside other treatments or on its own if the patient has chosen not to pursue standard treatment. Palliative care is intended to improve the quality of life for patients with serious conditions by focusing on treating emotional and physical symptoms.
This approach emphasizes the patient and his or her needs over targeting the disease itself. Palliative care is not the same thing as hospice, and may be beneficial for patients dealing with a severe illness—at any stage. Joining support groups or speaking with a counselor may also be helpful. In some cases, if your health is quickly declining, standard treatments may be too taxing on your body and lead to debilitating side effects.
If this is true, ask your doctor about lowering the treatment doses or receiving palliative care on its own. Lung cancer becomes more serious and difficult to treat as it progresses. Advanced or metastatic lung cancers of any kind tend to have very low survival rates. However, the cancer's stage—or how advanced it is—is a significant factor in your prognosis. One way to estimate life expectancy when battling cancer is to consider the five-year relative survival rate for that type of cancer.
A five-year relative survival rate shows the likelihood that a person with a specific type and stage of cancer would live for at least five years after the diagnosis, compared with people who don't have cancer. It's important to remember that these rates are based on patients who had advanced lung cancer at least five or more years ago, and the rates may not account for recent advances in treatment options.
The rates also don't consider all factors specific to each individual, such as the type of cancer and the care he or she is receiving.
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