Review articleNanotechnology is an important strategy for combinational innovative chemo-immunotherapies against colorectal cancer
Graphical abstract
Introduction
Colorectal cancer (CRC), also referred as bowel cancer, occurs when abnormal cells grow in the colon or rectum [1]. Approximately 96% of CRC are adenocarcinomas that result from the prolonged and slow growth of precancerous adenomatous polyps or adenomas, in the inner wall of the colon and rectum [2,3]. Among those, 10% may progress to invasive cancer [4,5]. Once established, those malignant cells can spread into the colorectum wall and potentially invade blood or lymph vessels, leading to metastases in distant organs and tissues, such as the liver, lungs, or peritoneum [1].
According to the American Joint Committee on Cancer, CRC can be classified into five stages (Fig. 1) [1,6].
A 5-year relative survival rate of 65% was obtained for patients diagnosed from 2006 to 2012 [7,8]. Even though, these survival rates change according to illness stage, being 90, 71 or 14% for CRC patients diagnosed with localized (39% of patients), regional or distant-stage disease, respectively [9].
Despite the recognized advances in the screening methods, surgical procedures and chemotherapeutic treatments currently available [10,11], approximately 20% of CRC patients at the time of the first diagnosis, and 30–50% after the surgical resection of the primary tumor, are diagnosed with the metastatic disease [12,13]. These patients with metastatic CRC present a median survival time lower than 8 months, in the absence of treatment.
This review summarizes the CRC biology and immunology, focusing on the immune and stromal cells with major role on the progression of this disease. It presents also an overview of the therapies approved for the CRC treatment, as well as the preclinical and clinical data available for the emerging approaches. We focus on the potential of nanotechnology-based technologies as cutting-edge combinational platforms to regulate the tumor-immune-stromal microenvironment, and thereby overcome CRC evasion and proliferation.
The discrepant CRC incidence rates worldwide are related to genetic and environmental factors, in addition to gender, age and ethnicity [14].
Genomic instability of several forms (Table 1) plays a significant role in the development of sporadic or inherited CRC, by facilitating the acquisition of genetic and epigenetic mutations in specific oncogenes and/or tumor suppressor genes by normal epithelial cells, thereby potentiating the colorectal epithelial cell transformation into adenocarcinoma and metastasis [[15], [16], [17]].
Seven tenths of all CRC are sporadic and usually derive from somatic mutations and dysfunctional Wnt/β-catenin signaling pathway [17]. But, 5% of CRC cases are a consequence of characterized hereditary syndromes derived from specific gene mutations [18].
The most common autosomal dominant inherited syndromes are the Lynch syndrome or hereditary nonpolyposis CRC (HNPCC), and the classical familial adenomatous polyposis (FAP). The first is associated with mutations in the genes MLH1 and MSH2, which are involved in the DNA mismatch-repair pathway, while the FAP is caused by mutations in the tumor suppressor gene APC [19]. HNPCC and FAP are responsible for 2–4% and <1% of all CRC cases, respectively [20,21]. Although less clinically defined, MUTYH-associated polyposis (MAP), usually associated with attenuated FAP and caused by autosomal recessive mutations in the base excision repair gene MUTYH, seems to promote the development of less adenomas in the large bowel [19,22].
About 30% of CRC patients present family CRC history, where the lifestyle risk factors add to the accumulation of usual genetic alterations over generations [18]. When compared to people without CRC family history, people with a first-degree relative present a higher risk of developing this disease [22].
In addition to the hereditary and family CRC history, individuals who have a personal medical history of adenomatous polyps, chronic inflammatory bowel disease (ulcerative colitis and Crohn's disease) characterized by a prolonged inflammation of the colon and rectal mucosa or full thickness of bowel wall, and type 2 diabetes have also an increased risk of developing CRC and other intestinal neoplasms than general individuals [23].
Several behaviors strictly related to sedentary lifestyle, long-term smoking and alcohol addiction, are known as CRC modifiable risk factors. Physically active or less sedentary people have a risk of colon cancer (but not rectal cancer) 25% lower than sedentary people [24]. Independently of the physical activity, obesity increases the risk in 50% and 20% for colon cancer, and 20% and 10% for rectal cancer, for men and women respectively, being responsible for nearly a third of CRC and lower survival likelihood [25].
Formation and growth of polyps have been associated with cigarette smoking [26], and some mutations caused by tobacco are less effectively repaired in the presence of alcohol intake [27]. CRC incidence is also strongly influenced by the diet, which has a large impact on the microbiome environment in the large intestine, and consequently, in the immune response, inflammation and tumor development [28]. In contrast to the reduced CRC risk associated with dietary fiber intake (vegetables and fruits) [29], diets rich in fat, red and processed meat are related with a raised risk [30].
Metastatic CRC (mCRC) is a prolonged and multifaceted process involving several cellular and molecular pathways. CRC metastases can be found in the peritoneum [31], lungs [32], bone [33,34] and brain [35,36]. However, liver is usually the most affected organ in mCRC and often the single site of metastasis. Liver metastases affect 20–25% of patients at initial diagnosis time and 40% of individuals after primary tumor resection [37,38]. High levels of the carcinoembryonic antigen (CEA), associated to several symptoms, such as nausea, jaundice, weight loss and pain in the right upper quadrant, may be related to the hepatic metastatic form of CRC [39]. Additionally, in contrast to lung metastasis that are commonly asymptomatic [32], peritoneal metastasis are associated to abdominal swelling and distress, nausea, vomiting, weariness and weight loss [31].
Most of the metastases presented by these mCRC patients cannot be addressed surgically, being rather treated with chemotherapy, alone or in combination with biological agents. Even though, a limited success has been achieved by these therapeutic combinations, which may be explained by the so-called “tumor immune microenvironment” (TIME) [40].
Similarly to other solid tumors, CRC TIME is a complex network of bidirectional interactions established between a complete set of stromal and immune cells, along the extracellular matrix, which can suppress and/or promote tumorigenesis via individual or collective functions. It has been associated with the multistep process from normal colonic epithelium to an adenomatous polyp, and ultimately to an invasive colon carcinoma [41].
The stroma plays an essential role in tumor architecture, providing a physical support for the functions of residing cells [42,43]. Stromal cells, such as endothelial cells (EC) (vascular or lymphatic), pericytes, and cancer-associated fibroblasts (CAF) have been identified as having an active role in CRC microenvironment (Fig. 2) [44].
The immune system itself is also an important contributor to the suppressive TIME. Despite the ability of the immune system to regulate the tumor biology and inhibit tumor development, both innate and adaptive immune cells can polarize from their “tumoricidal” form to their “tumorigenic” one within TIME, further influencing the growth, proliferation, and infiltration of other immune cells into the site of injury [45]. These cells include mostly the tumor-infiltrating lymphocytes (TIL; T cells, B cells, and natural killer (NK) cells), tumor-associated macrophages (TAM), mast cells, myeloid-derived suppressor cells (MDSC), granulocytes (neutrophils, eosinophils and basophils), and dendritic cells (DC) (Fig. 2) [46,47].
The major roles of each of the main individual components of the TIME is described in Table 2.
Another important component to take into consideration within the CRC microenvironment is the inflammation. The activation of this process is a major contributor to the TIME and subsequent tumorigenesis [46,47]. Currently, the chronic inflammation is well recognized as both a tumor initiator and promoter [77]. Additionally, inflammatory cells release several biomolecules, such as cytokines, chemokines, free radicals, prostaglandins, enzymes, and matrix metalloproteinases (MMP), that can induce genetic and epigenetic changes, which in turn may lead to tumor development and progression, resistance to apoptosis and angiogenesis [45,78]. Moreover, several intracellular signaling pathways are often dysregulated during chronic inflammation, which leads to abnormal expression of pro-inflammatory genes involved in malignant transformation [45,79]. On the other hand, inflamed stroma has been shown to promote the progression of colonic adenomas to adenocarcinomas in vivo [80]. However, it has also been observed that tumors that do not progress as a direct consequence of chronic inflammation (sporadic tumors) are also characterized by an inflammatory microenvironment [81].
Section snippets
Current chemotherapeutic-based established therapies against colorectal cancer
Chemotherapy is one of the major modalities of cancer treatment that uses cytotoxic drugs to suppress abnormal cell proliferation and induce apoptosis of damaged cancer cells.
CRC chemotherapy was initiated with the discovery of 5-fluorouracil (5-FU) by Heidelberger and colleagues in 1957 [82]. The anti-tumor efficacy, as well as the cytotoxicity of 5-FU administered as an intravenous bolus was demonstrated to be potentiated by the addition of the reduced folate leucovorin (LV; 5-formyl
Modulation of host immune system against colorectal cancer
Immunotherapy has been adopted as a therapeutic approach that harnesses host immune system to reduce or eliminate tumor cells [130]. Immunotherapy can be divided in active and passive approaches [131]. A temporary anti-tumor effect is normally obtained using a passive immunotherapeutic strategy, and therefore constant administrations are needed due to the nonexistence of immunological memory. Examples include the monoclonal antibodies directed to a specific target on a cancer cell, or against a
Combinational approaches for CRC destruction
Approximately 20% of these patients present metastases, especially in the liver and lungs. Chemotherapy, radiation, targeted therapies and immunotherapeutic strategies may be given alone or in combination to relieve symptoms and prolong survival in mCRC cases [179].
Nanotechnology as a promising strategy for CRC therapy
Nanomedicine comprises the application of nanotechnology to biomedicine and health sciences to diagnose, prevent and treat diseases, while allowing for a better understanding of the complexity of disease pathophysiology, yielding more effective therapies and improving patients' life quality. In this context and according to the European Science Foundation (ESF), nanomedicine uses nanoscale functional systems engineered with distinct materials and shapes, and developed within a controlled size
Conclusion
CRC prevention and screening programs have greatly contributed for the reduction of CRC incidence levels and death rates. However, these numbers are not so optimistic for patients under the 50's and limited effective therapeutic options are currently available to stop the progression of the metastatic disease.
Tumorigenesis is a complex and dynamic process that involve different cellular and non-cellular elements, and their interaction contribute to tumor development, progression, metastasis and
Acknowledgements
This project has been supported by the Fundação para a Ciência e Tecnologia-Ministério da Ciência, Tecnologia e Ensino Superior (FCT-MCTES), under the frame of EuroNanoMed-II (ENMed/0003/2015: HF, VP, DA; ENMed/0051/2016: HF, RS-F). AIM, BC, CP, JC and LM are supported by the FCT-MCTES (Fellowships PD/BD/113959/2015, SFRH/BD/131969/2017, SFRH/BD/87591/2012, SFRH/BD/87150/2012, SFRH/BPD/94111/2013, UID/DTP/04138/2019). This project has received funding from European Structural & Investment Funds
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