How Does the Aging Microenvironment Support Cancer Formation and Progression?

What Is the Tumor Microenvironment?

The tumor microenvironment (Tumor Microenvironment = TME) means the surroundings that nourish tumor tissue. It can therefore be defined as tissue near the tumor. It is a complex ecosystem containing many elements, including blood vessels, immune cells, fibroblasts, extracellular matrix, and cytokines.

The tumor microenvironment differs from the normal tissue environment (Normal Tissue Environment – NTE) in many respects, including tissue architecture, inflammatory reactions, oxygen and pH levels, cellular nutritional status, and tissue stiffness.

Whereas the normal tissue environment can suppress cancer growth during early tumor formation, the tumor microenvironment generally promotes cancer growth, although it can have some anticancer effects. It plays a particularly important role in producing and maintaining the cancer stem cells underlying cancer growth.

For this reason, converting the tumor microenvironment into normal tissue, or normalizing it, may inhibit cancer growth or improve the success of our anticancer treatments.

The Aging Tumor Microenvironment

An article published in Nature, a leading scientific journal, reviewed how the aging microenvironment may affect tumor progression. It specifically assessed the cellular and molecular changes occurring in noncancerous cells during aging and how these may contribute to a microenvironment permissive to tumor formation.

Cancer as a Disease of Old Age

Of all cancers, %65 occur in people over 65. Cancer is the leading cause of death in both men and women aged 60-79. Alongside these statistics, longer life expectancy made possible by developing technology will require improvements in health services. The World Health Organization (WHO) estimates that the world's population over 60 will increase by 2050 from % 12 to % 22, exceeding 2 billion. The resulting economic, health, and financial burdens on society are far from insignificant.

Human cancers are widely accepted to be genetic diseases caused by mutations. However, biological evolution also depends on mutations, and cancers are actually natural products or consequences of human evolution. Completely eliminating cancers at the expense of human evolution is impossible. Precisely for this reason, we need to learn not how to kill cancer, a very large group of diseases, but how to control it.

Many Biological Processes Are Similar in Aging and Cancer Formation

Both cancer and aging mechanisms underlie the time-dependent accumulation of cellular damage. Cell-based studies also reveal that many hallmarks of aging are shared with cancer. However, as an important distinguishing feature, many studies show that aging can significantly affect tumor microenvironment cells promoting tumor progression and metastasis are promoted by tumor microenvironment cells significantly affected by aging, according to many studies. Fibroblasts, the principal connective tissue cells, and immune cellsappear particularly susceptible to this age-related effect. Environmental factors encountered as we age, such as ultraviolet (UV) radiation, alcohol, smoking, and pollution, contribute to long-term DNA damage accumulation and other events related to cellular aging. Age-related deterioration in tissues and cells and the associated increase in cancer risk are well documented. Recent studies have begun to establish mechanistic links between an aged microenvironment and tumor initiation and progression. Age-related reprogramming of the stroma—the connective tissue mass surrounding and supporting the main cell population—within the tumor microenvironment is also an important cause of metastatic progression. Interestingly, conflicting statistics on age and disease outcomes have been reported for different cancer types. The aging tumor microenvironment also affects tumor cell responses to chemotherapy, targeted therapies, and immunotherapies.

Aging Supporting Tissue – When the House's Framework Ages…

Balance within the stroma, supporting tissue, plays an important role in tissue homeostasis. The stroma consists of various components, including fibroblasts, endothelial cells, pericytes, adipocytes, extracellular matrix (ExtraCellular Matrix = ECM), and immune cells. Fibroblasts, the principal connective tissue cells, are the most common stromal component in body tissues. They are essential for synthesizing extracellular matrix, including collagen, and for connective tissue's structural integrity, and also play important roles in wound healing and inflammation . Their dominant influence in regulating many of these processes occurs through secretion of soluble factors into the microenvironment. Changes occurring during aging differ between organ compartments; fibroblasts also age.

How Do “Good Genes” Become “Bad Genes”? Antagonistic Pleiotropy in Aging Stromal Environments

Antagonistic pleiotropy means a gene has beneficial effects early in life but harmful effects later. Aging is a classic example, and cells accumulate as we age. Although it is impossible to answer whether the initiation of aging in humans results directly from age or from other factors, we fundamentally know that aging cells accumulate in stromal microenvironments and tissues. How these cells accumulate remains debated, but the main idea is that declining immune function with age reduces recognition and clearance of these growth-arrested cells, causing their accumulation.

Extracellular Matrix and Aging

Besides secreted factors, fibroblasts also participate in laying down the extracellular matrix (ExtraCellular Matrix = ECM). ECM is responsible for the architectural integrity of most tissues and enables protein- and cell-specific exchange in the body. However, this matrix is highly dynamic, continuously remodeling while controlling a delicate balance between degradation and deposition. Loss of ECM integrity is a hallmark of cancer, and its disorganization is strongly associated with tumor progression and metastasis.

Diversity of Extracellular Matrix Components Between Organs

The ECM microenvironment differs greatly between organs because of the complex diversity required for specialized organ structure and function, and these factors change substantially with age. In healthy people, softer tissues such as brain and breast require a more elastic, looser connective tissue environment, while harder tissues such as skin and bone require stiffer structures to provide a protective barrier. This is achieved through cross-linking ECM components and regulating total collagen density. In skin, for example, collagen and elastin are tightly linked in a basket-weave pattern with the help of hyaluronic acid (HA). HA changes have been shown to increase fibroblasts' ability to contract elastin and collagen matrices. HA's role in cancer is also believed to be tissue-specific: reduced HA is associated with increased tumor formation in normally HA-rich tissues such as skin. Changes in ECM stiffness also have biophysical effects that can substantially alter cell shape.

Extracellular Matrix in Aging and Cancer

ECM integrity has clearly been shown to decline substantially with age. The best-known and most visible example is skin wrinkling. Studies of healthy young and old human fibroblast samples reveal that young dermal fibroblasts secrete higher levels of ECM components, including proteoglycans, glycoproteins, and cartilage-linking proteins, than old dermal fibroblasts. The most abundantly secreted ECM component from young fibroblasts is a protein called HAPLN1. HAPLN1 is a cross-linking protein initially thought to be secreted only by tumor cells and to contribute to tumor cell invasion. However, we see that HAPLN1 is secreted by young fibroblasts and that this secretion is lost from healthy aged human dermal fibroblasts—another observation illustrating the complex interactions between tumor cells and fibroblasts.

The Immune Microenvironment and Aging

Inflammation: A Driver of Age-Related Cancer Progression

The immune system plays a vital role in recognizing and inhibiting malignant tissue growth. Evading immune surveillance is therefore a critical step required for tumor initiation, growth, and progression toward metastasis. One hallmark of aging is an increase in inflammation / inflammatory responses , a process involving systemic low-grade chronic inflammation. This persistent inflammatory response can lead to tissue degeneration and disruption of acute inflammation and is severe. Cellular aging is considered an important factor linking inflammation with many age-related malignancies.

Age-Related Immunosenescence and Cancer

Immunosenescence is another factor contributing to many age-related pathologies, including cancer. It is defined as age-related dysregulation of the immune system, with declining immune cell subsets and overall immune function. The process results from factors including thymic atrophy, reductions in naive T cells, decreased memory T cell function, and reduced diversity of antigen recognition by T cells. Inflammation appears important in accelerating many of these processes because the associated chronic inflammatory signals and responses are frequently interrupted. Alongside loss of T cell function, natural killer cells, macrophages, and dendritic cells, involved early in tumor recognition and suppression, appear to lose their cytotoxic, cell-killing or function-inhibiting effects as we age.

Although neutrophils appear to undergo immunosenescence throughout aging, they have still been shown to infiltrate injured tissue in older people. Interestingly, studies show that neutrophils in older patients and mice produce more anti-inflammatory protein groups than those in younger patients.

Aging and Treatment Response

Cancer treatment presents many challenges in older patients. Age-related health conditions often leave clinicians uncertain whether potentially beneficial therapies can safely be given at standard doses, whether survival will improve, or whether adverse effects will affect quality of life. Approximately % 50 of cancers occur in patients over 65, and this is estimated to rise to % 70 as life expectancy continues increasing. However, clinical trial data for patients above this age are extremely limited. Only % 40 of cancer trial participants are over 65, and fewer than % 10 are over 75. Importantly, most preclinical studies use 6-8-week-old mice, substantially misrepresenting the actual clinical age of most cancer patients. Mice aged 18 months are considered more representative of older people, equivalent to humans aged 60, but may represent different age ranges for different organs. Understanding mechanisms underlying the aged tumor microenvironment and recent advances in treatment response may reveal important information for more effectively targeting cancer in older people.

Chemotherapy Response in Older Patients

Chemotherapy is a nonspecific, aggressive treatment targeting rapidly growing malignant cells. It can be used alone or combined with other targeted therapies. Given its limited specificity, many treatment-related adverse effects can be life-threatening in older individuals. Many examples show how an aged microenvironment may contribute to resistance to chemotherapy drugs. Aged components are already highly chemotherapy-resistant because they are not rapidly proliferating. These cells may also secrete factors supporting cancer cells' intrinsic resistance to chemotherapy.

Chemotherapy has been shown to accelerate immunosenescence further in older patients, thought to occur by increasing the rate of aging in microenvironments. Many cases show that chemotherapy is well tolerated in older patients and prolongs survival regardless of cancer location. When determining chemotherapy regimens for older patients, whether benefits outweigh adverse effects must be considered.

Targeted Therapy Response in Older Patients

Targeted therapy represents a personalized standard of care aimed at targeting cancer cells or the tumor microenvironment. Although many patients' tumors initially respond, a large proportion may later become resistant. The relationship between signaling pathway changes and the microenvironment in resistance to targeted therapy is poorly defined, especially regarding age. Targeted therapy generally has fewer off-target effects than chemotherapy or radiation therapy. Cells therefore appear to undergo more intrinsic changes involving genetic mutations, epigenetic alterations, and genomic instability to stimulate a resistant tumor environment.

Immunotherapy Response in Older Patients

Immunotherapies that regulate the immune microenvironment to target and eliminate tumor cells have revolutionized cancer treatment over the last decade; however, resistance to these treatments is also extremely important. Few direct studies evaluate immunotherapy effectiveness in aged cancer models. Observations suggest that older patients may respond less to immunotherapy for diseases such as lymphoma, glioblastoma, and leukemia.

Genetic and environmental diversity between patient populations also limits pooled analyses across racial and ethnic backgrounds. Nevertheless, given the inconsistency seen when targeting an immune checkpoint in aged models, specific immune-targeted treatments may need to be tailored by age. These emerging data emphasize the need for age-specific models in all cancer types. Clearly, targeting age-related changes in cancer may provide new ways to alleviate this growing public health burden.

Tumor Aggressiveness Is Not Always Related to Age

In many tumor types, age indicates a more aggressive tumor. However, for some cancers, such as breast and colon cancer, overall incidence is higher in older patients, while cancers diagnosed in younger patients are more aggressive and have worse outcomes. The reasons are not fully understood but may include:

Lack of Cancer Screening

Routine screening such as mammography and colonoscopy is not mandatory for young individuals. Consequently, cancers in young people will be recognized much later than those diagnosed through routine, regular screening.

Driver Mutations Promoting More Aggressive Disease

Driver mutations in BRCA1 and BRCA2 in breast cancer, and APC in colorectal cancer, may trigger early tumor manifestations. Depending on tumor subtype, tumors in young patients with breast and colon cancer may follow a more aggressive course.

Hormonal Effects

Breast cancer may be more susceptible to hormonal influences than other cancers such as melanoma; menstrual fluctuations may therefore affect its aggressive nature, while changes during menopause may reduce aggressiveness somewhat. Melanomas diagnosed during pregnancy have also been shown to be highly aggressive, and recent data suggest this results from abnormal estrogen receptor production and associated signaling.

Obesity

Obesity is a risk factor for cancer types, and obesity rates are rising rapidly in young patients. This may explain increasing cancer rates in the young population. In diseases increasingly seen in young adults, such as breast and colon cancer, obesity-related inflammation may increase their aggressiveness.