Cancers are complex tissues, consisting of multiple cell types organized within unique physiologic niches, or tumor microenvironments (TMEs). Conventional oncology therapies target rapidly dividing cancer cells or the process through which healthy cells become cancerous. More recently, greater understanding of TMEs has uncovered strategies for developing new treatments that disrupt both carcinogenesis and the physiologic niches that promote that process.
Cancerous tissues differ starkly from their healthy counterparts in their low oxygen content, low pH, and low glucose levels, conditions that are both dysregulatory and self-perpetuating. For example, low oxygen levels lead to the generation of free radicals, which promote DNA damage and further mutations, resulting in the emergence of cells that not only survive but thrive under these abnormal conditions. Nearby cells within the microenvironment also destabilize.
Dysregulation in cancer reaches beyond the immediate surroundings of the stroma and non-stromal microenvironment. It has been known for at least a decade that the immune system, whose assistance is essential in fighting cancers, may also promote metastasis through the initiation of undesirable inflammatory processes. The crosstalk between the TME and the immune response is therefore another potential target for cancer drug development.
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Learn more about the role of the tumor microenvironment in cancer cell proliferation, immune cell avoidance, and more. Despite obvious structural and cellular differences between cancers and normal tissues, the “instructions” conferred on this abnormal environment by the tumor itself is what sets TMEs apart from normal biological niches. These include directives for sustained proliferation and related signaling, evasion of growth suppression mechanisms (and thereby resistance to apoptosis), replicative immortality, and activation of invasiveness (metastases). Genomic instability, which facilitates the acquisition of these characteristics by cancer cells and their niches, promotes genetic diversity that leads to further abnormalities within the microenvironment and everything it interacts with.
TMEs: The Players
TME components include both tumor and non-cancerous cells in the vicinity, for example, endothelial cells and fibroblasts, plus connective tissue cells and the extracellular matrix that helps shape cells into tissues. Today, these components, known as the stroma, are considered essential but not sufficient for understanding TMEs. Cancer researchers also consider, as part of the TME, the many free-standing molecules (e.g., cytokines, proteases) and immune system cells (e.g., lymphocytes, macrophages) that infiltrate tumors and facilitate or inhibit disease progression.
These four components—non-cancerous cells, immune cells, molecular-level events, and the tumors themselves—are highly variable among patients exhibiting the same tumor type (e.g., breast, colon), at different disease stages in a single patient, and even within the same tumor. Their numeric variability, and how they communicate, confound scientists’ efforts to unravel the course of chemical signaling both within the tumor and between cancer cells and their surroundings. One such communication pathway involves transforming growth factor beta (TFG-β)—a molecule secreted by tumors that inhibits the growth of normal cells that might otherwise compete with cancers for nutrients and other resources related to survival and expansion.
The unique niches that tumors create to nourish, perpetuate, and proliferate also disrupt normal macromolecular homeostasis. Two typical components of the extracellular macromolecular microenvironment are immune system cells, neutrophils and macrophages. A group at Baylor discovered that, depending on the chemical messengers they produce, tumors may attract neutrophils to the exclusion of macrophages, or vice versa. This preference becomes an existential issue for the tumor, as macrophages may promote or inhibit tumor growth. Clearly, this particular immune cell component of the tumor niche could dictate which treatments are likely to induce remission and which might accelerate tumor growth.
Implications for treatment
The molecular and cellular disorder within TMEs, and the consequent disruption of normal intercellular communication, would alone be cause to investigate therapeutic approaches targeting the TME. Drug development focusing on the tumor microenvironment makes sense anatomically as well.
More than 90% of pancreatic tumors consist of stroma, which, together with fibroblasts, secretes growth factors that promote tumor growth. In many instances the stroma pervades the TME to such an extent that it prevents anticancer drugs from entering the tumor. In a review of TME-targeting clinical trials for pancreatic cancer, the authors found that one approach, inhibition of the vascular endothelial growth factor (angiogenesis) pathway, showed no benefit. Targeting hyaluronic acid—another player in the pancreated TME component—was promising but only when combined with conventional chemotherapy and only for patients with high hyaluronic acid levels.
The review authors stressed the need for trials that “stratify patients to identify subgroups” through biomarkers, imaging, or biopsy that are susceptible to specific TME targeting. “Only then can we make full use of our increased understanding of the pancreatic tumor stromal biology,” they write.
Similarly, the stroma of liver tumors includes hepatic cells, macrophages, and endothelial cells that influence pathogenesis, tumor initiation, progression, and metastasis. Liver cancer is tough to beat, especially after it has spread, but strategies targeting one or more stromal components might offer hope for long-term responses.
As researchers learn more about the TME, treatments will emerge for controlling the niche-specific conditions that promote growth and metastasis. Using such agents alongside conventional cytotoxic agents or emerging tumor-targeting therapies like antibody-drug conjugates has the potential to provide longer-lasting responses, perhaps turning more cancers into manageable diseases.
The question remains, as with every breakthrough in our understanding of cancer, whether targeting the TME will truly be transformative to the practice of oncology or just another interesting development. Although clinical research results are mixed and our understanding of TMEs is still in a primitive state, there is plenty to be excited about.
In a recent interview, Maria T. Diaz-Meco, Ph.D., a researcher specializing in cancer metabolism and signaling at Sanford Burnham Prebys Institute, described the emerging strategies for treating the stroma, particularly among TME components, as “the final frontier” in cancer therapy.
To learn more about the role of the tumor microenvironment in cancer cell proliferation, immune cell avoidance, and more, download our free eBook “Understanding Cancer through the Tumor Microenvironment” now.