Brain Metastasis of Colorectal Cancer: Microenvironment and Molecular Mechanism

Introduction

Colorectal carcinoma (CRC) is the third most commonly diagnosed cancer in males and the second most common in females worldwide. The main causes of failure for treatments are local recurrence and distant metastases, especially when vital organs such as liver and lung are involved through hematogenous dissemination. Brain metastasis is a much less common but more fatal condition and is usually considered as the late-stage manifestation for CRC. Compared with other malignancies such as lung cancer, breast cancer, and melanoma, the incidence of brain metastasis from CRC is considerably rare. Merely 0.3–9% of patients with CRC may develop brain metastasis synchronically or heterochronically, representing only 4–6% of all brain metastasis cases reported by . Lately, the incidence of brain metastasis has been increasing, owing to the improved detection methodology and/or local control of primary and secondary lesions, which prolongs the survival rate but at the same time increases the risk for developing brain metastases. As a result, the problem of brain metastasis from CRC should be ignored no longer.

Most brain metastases occur in the cerebral hemispheres (48–58%), followed by the cerebellum (18–43%), and 23–33% patients have multiple lesions. Brainstem metastasis of CRC is rare. Patients may complain about headache, motor disturbance, mental change, nausea or vomiting, seizure, aphagia, or visual disturbance according to the functional brain area involved ( ).

Once diagnosed with brain metastasis, the patient’s prognosis is not promising, with less than 6 months. Several prognostic factors for patients with brain metastasis of CRC have been identified, including age <65 years, shorter interval from CRC diagnosis to brain metastasis diagnosis, and more than three intracranial metastases. recently concluded that the amount of chemotherapy before brain metastasis was also an independent risk factor for overall survival.

Molecules associated with metastatic potential

The process of metastatic cascade includes local invasion, intravasation, dissemination, extravasation, and colonization at the target organ. As a matter of fact, specific tumor cell clones may tend to migrate and invade more; yet the microenvironment of target organ parenchyma may also alter the destination of the disseminated metastatic cells. This notion is the so-called seed and soil theory by Paget.

The primary tumor is usually genetically heterogeneous, consisting of cells with different potentials to migrate and metastasize. Genetic mutations make it possible for some of the cancer cells to gain the ability to metastasize ( Table 16.1 ), yet these malignant cells still need to conquer various environmental pressures (hypoxia, poor blood supply, growth suppressor genes, cell checkpoint, DNA damage system, and immune mediators) to successfully proliferate in the metastatic target organs.

Table 16.1

Genes Associated with Metastatic Potential of Colorectal Cancer

OMIM No.	Gene	Chromosome Location	Function(s) of Protein
107269	CD44	11pter-p13	An integral cell membrane glycoprotein with a postulated role in matrix adhesion lymphocyte activation and lymph node homing
114210	S100A4	1q21.3	Increases endothelial cell motility, increases invasive properties through deregulation of the extracellular matrix
120361	MMP-9	20q13.12	Extracellular matrix degradation
156490	NM23	17q21.3	A histidine kinase related to cell proliferative activity by phosphorylating KSR and leading to decreased ERK1/2 activation
190070	KRAS	12p12.1	Encode GDP/GTP-binding proteins involved in signal transduction in cellular proliferation, differentiation, and senescence
190090	SRC	20q11.23	Regulating cell division, motility, adhesion, angiogenesis, and survival
192240	VEGF	6p21.1	Angiogenic growth factor, controlling blood vessel formation and permeability
600687	TIAM1	21q22.11	Rac-specific guanine nucleotide exchange factor, directly mediate Ras activation of Rac.
600993	SMAD4	18q21.2	Transcription factor, pivotal role in signal transduction of TGFβ
	RHOGDI2	11p11.2	Regulates function of Rho and Rac, involved in cell signaling, proliferation, cytoskeletal organization, and secretion

Epidermal Growth Factor Receptor Signaling

Amplification and overdose of epidermal growth factor receptor (EGFR) were identified in several brain metastatic solid tumors, indicating that EGFR mutations and amplification are involved in the tumorigenesis of brain metastasis. investigated the difference of EGFR statuses between primary CRC and corresponding metastatic sites (liver, lung, bone, and brain). In 19 of 53 primary tumors expressing EGFR, the corresponding metastatic site was found negative, whereas it was found positive in 15% metastases from EGFR-negative primary cancers. The irrelevance of EGFR status in primary and metastatic CRC can explain the fact to some extent that some CRC patients cannot have a good prognosis after EGFR-targeted monoclonal antibodies; moreover, the metastatic CRC may alter its biophenotype such as EGFR status to survive from immune elimination and chemotherapeutants.

The mutation of KRAS gene, a member of the rat sarcoma virus gene family of downstream genes of EGFR, devotes most part of mutated genes in the EGFR signaling pathway (35–45% of all CRC), which strongly correlates with poorer outcomes in patients with CRC ( ). found that KRAS mutation prevalence was high in CRC patients presenting with brain metastases compared with primary cancer, and even higher than that in liver metastases. These results revealed the importance of KRAS signaling in formation of brain metastasis from CRC.

Other Metastasis Promoters

CD44

CD44 is an integral membrane glycoprotein that functions as a receptor for the extracellular matrix glycan. The standard isoform is designated CD44s. CD44 splice variants containing variable exons are designated CD44v. CD44 is frequently expressed on primary brain tumors and brain metastases. CD44v expression was weak in primary brain tumors and cell lines derived from normal brain and tumor tissue. However, high levels of isoforms were shown in all metastatic brain tumors. The expression level of CD44s and CD44v6 in CRC were significantly higher in primary tumors as compared to their metastases. Interacting the CD44-associated signaling by inhibition of fatty acid synthase would reduce metastasis in CRC, which suggests a potential treatment strategy for advanced CRC ( ).

Rho GDP Dissociation Inhibitor 2

The potential effect of Rho GDP dissociation inhibitor 2 (RhoGDI2) on cancer cell metastasis was first presented in human bladder cancer cell lines. RhoGDI2 was an independent prognostic factor for relapse-free survival of CRC in a multivariate analysis. It functions as GTP-binding proteins of the Ras superfamily and regulates the development of numerous aspects of the malignant phenotype, including cell cycle progression, resistance to apoptotic stimuli, neovascularization, tumor cell motility, and invasiveness. Upregulation of RhoGDI2 would lead to a low activity of Rac and Cdc42 and rector-dependent deficiency in cell migration ( ), and enhance the cell proliferation, motility, and invasion in vitro .

Smad4

Smad4 plays a pivotal role in transforming growth factor beta (TGF-β)/Smad signaling pathway, regulating cell proliferation, differentiation, and apoptosis. Knockdown of Smad4 results in loss of a tumor-suppressive function of TGF-β only, that is, cell cycle arrest, but has no effect on EMT induced by TGF-β in concert with the Ras/Erk pathway ( ). Loss of Smad4 might underlie the functional shift of TGF-β from a tumor suppressor to a tumor promoter ( ).

The protein level of Smad4 in lymph node metastases and liver metastases of CRC was significantly lower than in primary tumors. Suppressing Smad4 may enhance the proliferation, migration, and invasion of the HCT116 cell line. Papageorgis et al. (2011) found that loss of function of Smad4 and retention of intact TGF-β receptors could synergistically increase the levels of vascular endothelial growth factor (VEGF), enhanced migration of CRC cells with a corresponding increase in matrix metalloprotease-9 enhanced hypoxia-induced GLUT1 expression, increased aerobic glycolysis, and resistance to 5’-fluoruracil-mediated apoptosis.

Nonmetastatic Protein 23

Nonmetastatic protein 23 (NM23) gene was isolated as a putative metastatic suppressor gene. NM23-H1 is one isotype of the human NM23 gene. Breast cancer with a low expression of NM23 appeared to be more at risk for developing brain metastases. found that NM23-H1 strongly inhibited the liver metastasis of HT-29 cells in nude mice and inhibited the epidermal growth factor-induced cell migration in vitro . And NM23-H1 expression negatively correlated with intratumoral microvessel density (MVD), suggesting that NM23 may play its tumor-suppressive effect by inhibiting neoplastic angiogenesis. According to the result of a tissue microarray with 130 CRC patients, NM23 expression was higher in the cancer tissue than in adjacent nonneoplastic mucosa, and patients with higher NM23 protein intensity turned out to have a longer disease-free survival. However, no significant difference was found between primary and metastatic CRC tissue, which implies that increased NM23 may be important only in the early stage of CRC.

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