Fibrosis and cancer intersection

Introduction

Despite the decrease in cancer related deaths over the past 30 years, the incidence of six of the top ten cancers is increasing; breast, prostate, uterus, melanoma, pancreas, and colorectal cancer [1]. This alarming statistic raises the question of what has changed in recent years and supports the timeliness of this collection of articles that consider the role of fibrosis in cancer. If fibrosis is a precursor to cancer as has been suggested [2], is more fibrosis causing an increase in cancer now? Is it that fibrosis is associated with aging and the population is aging? Does the cancer in fibrosis act differently than cancer occurring in a non-fibrotic microenvironment? If we prevent fibrosis, will we prevent some cancers? The answers to these questions impact how we treat cancer and may provide the key for cancer prevention.

Background and significance

Fibrosis occurs in nearly every organ. Recurrent patterns emerge with persistent inflammation leading to scar formation as was clearly demonstrated during the COVID-19 pandemic [3]. Inflammation leading to fibrosis occurs in the lungs with acid reflux and environmental toxins causing irritation and ultimately scarring [4]. Acid reflux leads to esophageal inflammation and the scarring of Barrett’s esophagus [5]. Helicobacter pylori leads to inflammation of the gastric antrum and fibrosis with resultant B12 deficiency [6]. Ulcerative colitis leads to inflammation and results in scarring with the classic lead pipe deformity of the colon on barium exam [7]. Hepatitis can lead to liver cirrhosis [8], pancreatitis may lead to pancreatic fibrosis [9], chronic cystitis leads to a fibrotic bladder [10]. Renal inflammation leads to scaring [11]. Inflammation leading to fibrosis occurs in the eye, mouth, heart, and breast. Inflammation leading to fibrosis a recurrent theme throughout the body.

Is there more fibrosis now? What is the role of aging?

The number of patients with GERD continues to increase from nearly 450 million in 1990 to nearly 800 million in 2019 [12]. Helicobacter pylori currently effects 90% of population in developing countries with a significant annual recurrence rate [13]. Ulcerative colitis had an increasing prevalence of up to 5 million cases in 2023 [14]. Cirrhosis has increased by 13% since 2000 due to drug use, alcohol addiction, and metabolic syndrome [15]. Pancreatitis is increasing due to increasing obesity, diabetes, gallstones and advanced age [16]. UTIs are increasingly common affecting 12% of women and 3% men [17]. The incidence of Staphylococcus infection-associated glomerulonephritis (SAGN) cases increased due to drug-resistant Staphylococcus aureus infections [18]. Pulmonary fibrosis is increasing as our population ages [19].

Does the cancer in fibrosis act differently than cancer occurring in a non-fibrotic microenvironment?

We investigated lung cancer in a fibrotic and non-fibrotic background. Our results showed that squamous cell carcinoma was more frequently seen in the fibrotic lung and had shorter doubling times [20]. Nodules occurring in fibrosis were more likely to be lung cancer, challenging traditional screening algorithms [20]. If screening once a year for lung cancer in patients with emphysema decreases mortality, then we may need to screen more frequently for patients with lung fibrosis who are at increased risk of developing cancers with shorter doubling times. Cancer in a background of fibrosis is more likely to metastasize which may be in part due to fewer blood vessels and therefore the decreased ability of the body to keep the tumor from spreading [21].

If we prevent fibrosis, will we prevent some cancers?

In the lung, pirfenidone decreases collagen deposition in patients with pulmonary fibrosis. Miura showed reduced lung cancer in patients taking antifibrotic pirfenidone [22]. Ying reports decreased radiation induced lung fibrosis by inhibition of TGF-B1 [23]. Also, pirfenidone decreases exacerbations associated with surgery in patients with pulmonary fibrosis [24]. Breast density represents the extent of collagen in breast tissue. Göransson demonstrated how tamoxifen treatment reduced collagen organization and tissue stiffness in the normal breast [25]. Bäcklund reports the time to mammographic density decrease after Tamoxifen [26]. Kisseleva and Caligiuri describes liver fibrosis and its regression [27-28]. Mesenchymal stromal cells are a promising treatment for liver cirrhosis [29]. Decreasing fibrosis could prevent cancer occurrence.

Future directions

Early diagnosis of cancer could be improved with early diagnosis of fibrosis and radiology plays a central role with changes occurring before clinical symptoms. Each organ has a manifestation of fibrosis which typically involves organ shrinkage, duct dilatation and central arterial enlargement [30-32]. Advances in artificial intelligence may help with early fibrosis diagnosis and early cancer identification [33]. Zhang describes communication between cancer-associated fibroblasts and tumor microenvironment in breast cancer metastasis [34]. Collagen could be targeted to treat cancer [35]. Myofibroblast targeting could limit fibrosis as well as tumor progression [36]. Prostate cancer behavior can be manipulated by targeting stroma to overcome the limitations of current treatments [37]. Anti-TGF-B therapies in combination with traditional treatment may lead to improved outcomes [38].

Conclusions

We must move beyond early detection of cancer to cancer prevention. Chemoprevention may include strategies to slow down or reverse fibrosis as has been shown with antifibrotic treatments in the lung, liver and breast. The future success in the battle against cancer must include a combination approach of limiting inflammation, reversing scarring and detecting cancer at its earliest stage.