Tumor microenvironment

The tumor microenvironment is the cellular environment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, other cells, signaling molecules, and the extracellular matrix (ECM).[1] The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells, such as in immuno-editing. The tumor microenvironment has been shown to contribute to tumour heterogeneity. In one of its earliest forms, this concept of interplay between the tumor and its microenvironment can be seen in Stephen Paget's "seed and soil" theory where he postulated that metastases of a particular type of cancer ("the seed") often metastasizes to certain sites ("the soil") based on the similarity of the environments of the original and secondary tumor sites.[2] Later, experiments by Halachmi and Witz in mice showed that for the same cancer cell line, inoculation in mice (where the tumor microenvironment could affect the cancer) created greater tumorigenicity than the same strain inoculated in in vitro culture.[3][4]

Vasculature in the tumor microenvironment

80-90% of cancer are carcinomas, or cancers that form in the epithelial tissue.[5] This tissue is not vascularized, which prevents tumors from growing greater than 2mm in diameter without recruiting new blood vessels to feed itself.[6] The process of angiogenesis is dysregulated to feed the cancer cells, and as a result the vasculature formed differs from that of normal tissue.

Enhanced permeability and retention effect

The enhanced permeability and retention effect (EPR effect) is the observation that the vasculature of tumors is often leaky and accumulates molecules in the blood stream to a greater extent than normal tissue. This effect linked to inflammation is not only seen in tumors, but in hypoxic area of cardiac muscles following a myocardial infarction (MI or heart attack).[7][8] This leaky vasculature is thought to have several causes, including a dearth of pericytes and a malformed basement membrane.[8]

Hypoxia

The tumor microenvironment is often hypoxic. As the tumor mass increases, the interior of the tumor grows farther away from existing blood supply. While angiogenesis can reduce this affect, the partial pressure of oxygen is below 5 mm Hg (venous blood has a partial pressure of oxygen at 40 mm Hg) in more than 50% of locally advanced solid tumors.[9][10] The hypoxic environment leads to genetic instability, which is associated with cancer progression, via downregulating nucleotide excision repair (NER) and mismatch repair (MMR) pathways.[11] Hypoxia also causes the upregulation of hypoxia-inducible factor 1 alpha (HIF1-α), which induces angiogenesis, and is associated with poorer prognosis and the activation of genes associated with metastasis.[10]

While a lack of oxygen can cause glycolytic behavior in cells, tumor cells have also been shown to undergo aerobic glycolysis as well, in which they preferentially produce lactate from glucose even when there is abundant oxygen. This phenomenon is called the Warburg effect, in honor of its discoverer, Otto Warburg.[12] No matter the cause, this leaves the extracellular microenvironment acidic (pH 6.5-6.9), while the cancer cells themselves are able to remain neutral (ph 7.2-7.4). It has been shown that this induces greater cell migration in vivo and in vitro, possibly by promoting degradation of the ECM.[13][14]

Reactive stromal cells and the microenvironment

The stroma of a carcinoma is the connective tissue below the basal lamina. This includes fibroblasts, ECM, immune cells, and other cells and molecules. The stroma surrounding a tumor often reacts to the intrusion via inflammation, similar to how it might with a wound, leading cancer to be called "wounds that do not heal."[15] Inflammation can encourage angiogenesis, speed the cell cycle, and prevent cell death, all of which augments tumor growth.[16]

Carcinoma associated fibroblasts

Carcinoma associated fibroblasts (CAFs) are a heterogenous group of fibroblasts whose function is pirated by cancer cells and then contribute toward carcinogenesis[17] These cells usually are derived from the normal fibroblasts in the surrounding stroma but can also come from pericytes, smooth muscle cells, fibrocytes, mesenchymal stem cells (MSCs, often derived from bone marrow), or via epithelial-mesenchymal transition (EMT) or endothelial-mesenchymal transition (EndMT).[18][19][20] Unlike their normal counterparts, CAFs do not retard cancer growth in vitro.[21] Beyond simply lacking the ability of tumor inhibition, CAFs also perform several functions which support tumor growth, such as secreting vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), platelet-derived growth factor (PDGF), and other pro-angiogenic signals to induce angiogenesis.[9] CAFs can also secrete transforming growth factor beta (TGF-β), which is associated with EMT, a process by which cancer cells can metastasize,[22] and is associated with inhibiting cytotoxic T cells and natural killer T cells.[23] As fibroblasts, CAFs are able to rework the ECM to include more paracrine survival signals such as IGF-1 and IGF-2, thus promoting survival of the surrounding cancer cells.[17] CAFs are also associated with the Reverse Warburg Effect where the CAFs perform aerobic glycolysis and feed lactate to the cancer cells.[17]

Several markers are used to identify CAFs including expression of α smooth muscle actin (αSMA), vimentin, platelet-derived growth factor receptor α (PDGFR-α), platelet-derived growth factor receptor β (PDGFR-β), fibroblast specific protein 1 (FSP-1), and fibroblast activation protein (FAP).[19] None of the factors can be used to differentiate CAFs from all other cells by itself.

Myeloid-derived suppressor cells and tumor associated macrophages

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells of myelogenous origin with the potential to repress T cell responses. They regulate wound repair and inflammation and are rapidly expanded in cancer, correlating with that signs of inflammation are seen in most if not all tumor sites.[24][25] Tumors can produce exosomes that stimulate inflammation via MDSCs.[26][27] This group of cells include some tumor associated macrophages (TAMs).[24] TAMs are a central component in the strong link between chronic inflammation and cancer. TAMs are recruited to the tumor as a response to cancer associated inflammation.[28] Unlike normal macrophages, TAMs lack cytotoxic activity.[29] TAMs have been induced in vitro by exposing macrophage progenitors to different immune regulatory cytokines, such as interleukin 4 (IL-4) and interleukin 13 (IL-13).[17] TAMs gather in necrotic regions of tumors where they have been associated with hiding the cancer cells from normal immune cells by secreting interleukin 10 (IL-10),[30] aiding angiogenesis by secreting vascular endothelial growth factor(VEGF) and nitric oxide synthase(NOS),[9] supporting tumor growth by secreting epidermal growth factor (EGF)[30] and remodeling the ECM.[9] TAMs show sluggish NF-κB activation, which allows for the smoldering inflammation seen in cancer.[31] An increased amount of TAMs is associated with worse prognosis.[32][33] TAMs represent a potential target for novel cancer therapies.

TAMs have recently been associating with using exosomes (vesicles used by mammalian cells to secrete intracellular contents) to deliver invasion-potentiating microRNA (miRNA) into cancerous cells, specifically breast cancer cells.[26][34]

Tumor infiltrating lymphocytes

Tumor infiltrating lymphocytes (TILs) are lymphocytes that penetrate a tumor and while have a common origin with myelogenous cells at the hematopoietic stem cell, diverge in development. Concentration is generally positively correlated.[30] However, only in instances of melanoma has autologous transplant of TILs been used successfully as a means of treatment.[35] Cancer cells have been shown to induce apoptosis of activated T cells (a class of lymphocyte) by secreting exosomes containing death ligands such as FasL and TRAIL, and via the same method, turn off the normal cytotoxic response of natural killer cells (NK cells).[27][36] This suggests that cancer cells actively work to restrain TILs.

Extracellular matrix remodeling

Fibroblasts are in charge of laying down most of the collagens, elastin, glycosaminoglycans, proteoglycans (e.g. perlecan), and glycoproteins in the ECM. As many fibroblasts are transformed into CAFs during carcinogenesis, this reduces the amount of ECM produced and the ECM that is produced can be malformed, like collagen being loosely woven and non-planar, even curved.[37] In addition, CAFs produce matrix matrix metalloproteinases (MMP), which cleave the proteins within the ECM.[9] CAFs are also able to disrupt the ECM via force, generating a track that a carcinoma cell can follow directly behind.[38] In either case, destruction of the ECM allows cancer cells to escape from their in situ location and intravasate into the blood stream where they can metastasize systematically. It can also provide passage for endothelial cells to complete angiogenesis to the tumor site.

Destruction of the ECM also modulates the signaling cascades controlled by the interaction of cell-surface receptors and the ECM, and it also reveals binding sites previously hidden, like the integrin alpha-v beta-3 (αVβ3) on the surface of melanoma cells can be ligated to rescue the cells from apoptosis after degradation of collagen.[39][40] In addition, the degradation products may have downstream effects as well that can increase tumorigenicity of cancer cells and can serve as potential biomarkers.[39] The destruction of the ECM also releases the cytokines and growth factors stored therein (for example, VEGF, basic fibroblast growth factor (bFGF), insulin-like growth factors (IGF1 and IGF2), TGF-β, EGF, heparin-binding EGF-like growth factor (HB-EGF), and tumor necrosis factor (TNF), which can increase the growth of the tumor.[37][41] Cleavage of ECM components can also release cytokines that inhibit tumorigenesis, such as degradation of certain types of collagen can form endostatin, restin, canstatin, & tumstatin, which have antiangiogenic functions.[37]

Stiffening of the ECM is associated with tumor progression.[42] This stiffening may be partially attributed to CAFs secreting lysyl oxidase (LOX), an enzyme that cross-links the collagen IV found in the ECM.[19][43]

Clinical implications

Drug development

Numerous high throughput screens for cancer therapeutics are performed in vitro on cancer cell lines without the accompanying microenvironment, but current studies are also investigating the effects of supportive stroma cells on the biology of cancer cells and their resistance to therapy.[44] These studies revealed that there are interesting therapeutic targets in the microenvironment like integrins or chemokines.[44] These were missed by initial screens for anti-cancer drugs and might also help explain why so few initially identified drugs are highly potent in vivo.

Much effort has been devoted into developing nanocarrier vehicles (~20-200 nm in diameter) for transportation of drugs and other therapeutic molecules, so that these therapies can be targeted to selectively extravasate through tumor vasculature via the EPR effect. Using a nanocarrier is now considered the gold standard of targeted cancer therapy because it targets almost all tumors besides those few that are hypovascularized, like prostate and pancreatic tumors.[8][45] These efforts include protein capsids[46] and liposomes.[47] However, as some important, normal tissues, like the liver and kidneys, also have fenestrated endothelium, great care must be taken with using the correct size (10-100 nm, with greater retention in tumors seen in using larger nanocarriers) and charge (anionic or neutral).[8] Lymphatic vessels do not usually develop with the tumor, leading to increased interstitial fluid pressure, which made abrogate the journey of these nanocarriers to the tumor.[8][48]

Current Therapies

Bevacizumab is clinically approved to treat a variety of cancer by targeting VEGF-A, which is produced by both CAFs and TAMs, thus slowing angiogenesis. Many other small molecule inhibitors exist that block the receptors for the growth factors released, thus making the cancer cell deaf to much of the paracrine signaling produced by CAFs and TAMs. These inhibitors include Sunitinib, Pazopanib, Sorafenib, and Axitinib, all of which inhibit platelet derived growth factor receptors (PDGF-Rs) and VEGF receptors (VEGFRs). Cannabidiol, a cannabis derivate without psychoactive side effects, has also been shown to inhibit the expression of VEGF in Kaposi's sarcoma cells.[49]

Natalizumab is a monoclonal antibody that was designed to target one of the molecules responsible for cell adhesion (integrin VLA-4) and has promising in vitro activity in B cell lymphomas and leukemias.[44]

Also, Trabectedin is known to have immunomodulatory effects that inhibit TAMs.[30]

Current formulations of liposomes encapsulating anti-cancer drugs for selective uptake to tumors via the EPR effect include: Doxil and Myocet, both of which encapsulate doxorubicin (a DNA intercalator and common chemotherapeutic); DaunoXome, which encapsulates daunorubicin (another DNA intercalator similar to doxorubicin); and Onco-TCS, which encapsulates vincristine (a molecule which constitutively induces formation of microtubules, dysregulating cell division). Another novel utilization of the EPR effect comes from Protein-bound paclitaxel (marketed under the trade name Abraxane) where paclitaxel (a molecule which dysregulates cell division via stabilization of microtubules) is bound to albumin to add bulk and aid delivery.

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