Tumor Microenvironment and the Immune System Pathway

For many years, malignant cells have been the main source of interest in cancer research since they enable the independent growth and survival of tumor cells. Yet malignant cells alone do not provide all the answers because tumors also need support from a range of surrounding cells.

Tumors can often be thought of as masses of malignant cells, but rather than being self-sufficient and autonomous structures, they need the support of the surrounding non-malignant cells to survive and proliferate.

This assortment of non-malignant and malignant cells works together to invade tissues, induce angiogenesis, promote tumor growth, form metastases, and resist cell death, all the while evading the intense monitoring of the immune system (Hanahan and Coussens, 2012).

In order to build a powerful support system, malignant cells have to enlist non-malignant cells from inside the stromal tissue – the cellular environment for tumor development; this stromal tissue would otherwise work to inhibit the development of cancer.

Vascular endothelial cells (Junttila and de Sauvage, 2013), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) are major stromal cells. Tumor microenvironment (TME) refers to the zone where these cells interact with one another as well with the extracellular matrix (ECM).

Complex intra- and intercellular cellular signaling between stromal and malignant cells are involved in the process of recruiting and maintaining a host of non-malignant cells. Chemokines, cytokines, and growth factors, which are aberrantly expressed by cancer cells, activate the supporting cells to secrete more quantities of bioactive molecules.

These molecules, in turn,can act in a paracrine, autocrine, or juxtacrine way to assist with processes that are critical for cancer development; immune avoidance, metastasis¸ and tumor vascularization, for example.

Roles of the tumor microenvironment during vascularization

Similar to internal body organs needing a steady supply of blood to function in a normal way, a growing tumor also needs a constant blood supply in order to provide blood-borne mitogens and oxygen, as well as remove toxic metabolites. As a result, angiogenesis and vasculogenesis are required for tumor growth; the former refers to the formation of new blood vessels and the latter is the reorganization of existing blood vessels.

The formation and maintenance of tumor blood vessels are controlled by the TME. Cytokines and multiple growth factors work together to prevent anti-angiogenic pathways and encourage pro-angiogenic signaling. Major factors include:

• epidermal growth factor (EGF)
• vascular endothelial growth factors (VEGF)
• platelet-derived growth factor (PDGF)
• fibroblast growth factor (FGF)
• hepatocyte growth factor (HGF)
• transforming growth factor-β (TGFβ)

The ECM is a network of proteins that keep stromal cells in place. Remodeling of the ECM is crucial to accommodate vessels that are newly formed. This restructuring is catalyzed by serine, cysteine proteases, and metalloproteases released by fibroblasts and supporting immune cells. In addition, extra mitogens that are sequestered in the ECM are released by these proteases, which further stimulate tumor growth (Hanahan and Coussens, 2012).

The physiological nature of tumor-related blood vessels makes them crucial for tumor growth, and they also assist with immune avoidance and metastasis.

First, blood vessels that develop in and around tumors are unstable and disordered, which is attributed to prolonged activation of angiogenic pathways. Such blood vessels also exhibit a ‘leaky’ morphology due to limited pericyte coverage and poor endothelial cell junctions (McDonald and Baluk, 2002). As a result of this structure, tumor-supporting immune cells accumulate and malignant cells are allowed to metastasize to various parts of the body.

Second, high endothelial venules (HEVs) offer an important means of access to cytotoxic immune cells during normal immune surveillance. However, HEVs do not exist in tumor-associated vessels, which inhibit the accumulation of cytotoxic immune cells (for example, cytotoxic T lymphocytes, natural killer cells etc.) within the TME to destroy the tumor cells (Fisher et al., 2011).

Growth factors from the TME support tumor growth and metastasis

With the aid of tumor-supporting cells, malignant cells proliferate and enter the bloodstream, where they form metastases. For instance, in addition to encouraging angiogenesis, VEGF signaling also loosens tight junctions present between the endothelial cells and enables the cancer cells to migrate to the blood stream (Weis et al., 2004).

There are also other growth factors that aid the survival, proliferation, invasion, and metastasis of cancer cells. EGF signaling, for instance, plays an integral role in cancer progression as well as epithelial-to-mesenchymal transition (EMT) that is necessary for metastasis. Aberrant EGF signaling, together with over-production of EGF, can be activated by over-expression of EGFR – the membrane-bound receptor of EGF– either by hypoxia or gene mutation (Franovic et al., 2007).

CAFs help in tumor development by producing the permissive stroma required for tumor survival (Pietras et al., 2008). PDGF can function as a chemo-attractant for these CAFs. Multiple factors are secreted by

CAFs that potentiate cancer progression, including HGF (which stimulates the c-Met receptor and activates both invasion and proliferation) and TGFβ (which stimulates EMT pathways in tumor cells and makes these cells more invasive and likely to metastasize (Grugan et al., 2010, Yu et al., 2014). Cytotoxic immune cells can be inhibited by TGFβ from destroying the cancer cells.

Contribution of immune cells to the tumor microenvironment

The immune system, under normal conditions, acts as an ally, destroying pathogens and inhibiting diseases. However, tumors recruit cells of the immune system and convert them into an enemy from within.

A wide range of myeloid and lymphoid lymphocytes is present in cancerous lesions. These hijacked tumor-associated immune cells do not induce cell death, but secrete proteases and growth signals to promote cancer progression. Both proteases and growth signals stimulate the formation of tumor blood vessels and promote the growth of cancer cells. Key factors include:

• chemokines
• interleukins (ILs)
• tumor necrosis factor-α (TNFα)
• EGF
• VEGF
• FGF
• PDGF
• TGFβ

Tumor-supporting immune cells persistently express these factors that stimulate the formation of tumor blood vessels and promote the growth of cancer cells (Hanahan and Coussens, 2012).

Successful immune avoidance is also required by tumor growth. So, how does the TME aid malignant cells to evade destruction by cells of the immune system?

A range of factors that guard cancer cells from immune detection is secreted by the supporting immune cells. The secretion of CXCL12 by CAFs is one such example. The chemokine CXCL12 coats cancer cells and prevents cytotoxic T lymphocytes from destroying these cells (Feiga et al., 2013).

By suppressing cell death pathways, supporting immune cells can also promote the survival of tumor cells. The expression of integrin a4 by TAMs is an example of this mechanism which is capable of forming a complex with vascular cell adhesion molecule-1 (VCAM1). This VCAM1, in turn, suppresses apoptosis in metastatic breast cancer cells (Chen et al., 2011).

Summary

The TME contains a wide range of support cells, which are destroyed by the cancer cells to aid tumor progression. Immune cell avoidance and survival, proliferation of cancer cells, and survival are controlled by the TME. In future, it will be interesting to see how scientists dissect the intricate interaction of the tumor, immune cells, and stromal cells within the TME, and how those findings translate into novel therapeutics that target the TME’s cancer-supporting aspects.

References

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